Adams-Oliver syndrome . Terminal transverse limb defect in AOS: The toes are reduced to stubs (Photo courtesy Dr. P. Vijayalakshmi, Aravind Eye Care System, Madurai)
Neurological abnormalities include encephalocele (uncommon), intellectual disability (uncommon), seizures, hypotonia, developmental delay, enlarged ventricles, periventricular calcifications, cerebral hemorrhage and/or periventricular leukomalacia (PVL ). PVL may be due to vascular disruption and decreased perfusion during critical periods of fetal brain development . Neuronal migration abnormalities such as cortical dysplasia, pachygyria and polymicrogyria have also been reported . Hypoplasia of the corpus callosum has been reported . Absence of the superior sagittal sinus also supports the theory of embryonic vascular disruption in the pathogenesis of this syndrome [19–22].
Santos et al. first suggested that cardiac abnormalities could be a part of this syndrome . Approximately 10–20 % individuals with this syndrome might have congenital heart anomalies, mostly involving obstructive lesions on the left side of the heart . Other cardiovascular malformations such as bicuspid aortic valve, atrial septal defect, Shone’s complex, aortic valve stenosis , hypoplastic left heart syndrome, double outlet right ventricle, coarctation of aorta , ventricular septal defect [25, 26] and tetralogy of Fallot have been reported . Portal hypertension and pulmonary hypertension may occur [2, 27].
The following less consistent abnormalities have also been reported: oligohydramnios, upper limb micromelia, palatal or auricular malformations, anatomic bronchial anomalies, renal anomalies and craniofacial anomalies with frontonasal cysts .
Other findings include cutis marmorata telangiectasia congenita (CMTC) , abnormal pulmonary and portal vasculature, and necrosis of the abdominal skin and gangrene of digits and optic disc drusen. Several theories have been postulated to explain the pathogenesis of the observed defects seen in AOS. Early embryonic vascular disruption or insufficiency is considered to the most plausible mechanism . AOS is considered to result from ischemia, necrosis, and resorption of structures after an intrauterine vascular event affecting the brachial artery. This is further supported by the occurrence of several vascular malformations and clinical features.
Hypertelorism, narrow palpebral fissures, blue sclera, strabismus, microphthalmia, nuclear and anterior polar congenital cataract, retinal dystrophy, congenital vitreoretinal abnormalities, optic disc drusen and congenital optic atrophy have been reported uncommonly [29, 30]. Peripheral avascular retina with capillary dropout, arteriovenous anastomosis, and telangiectasia has been observed . Microphthalmia, microcornea and partial scleralization of the cornea were reported in the other eye. Congenital retinal non-attachment and falciform fold have also been reported . Eyes with optic disc drusen often tend to show abnormal angiogram patterns such as abnormal branching pattern on the disk, increased capillarity and relatively large blood vessels connecting the superficial and deep disk circulations.
There are no specific clinical diagnostic criteria due to the heterogeneity in clinical presentation. Some of the important differential diagnoses include the syndrome of scalp defect and split-hand defect, amniotic band sequence and focal dermal hypoplasia (Goltz suyndrome ) and  Genetic testing offers the definitive diagnosis, although it is expected that other genes are yet to be identified.
The main concerns depend on the severity of the scalp defect. The major concern is an open scalp lesion especially when associated with absent of parts of the skull. The risk for developing sepsis and/or meningitis in such patients is high. If the scalp defect is small, recovery occurs with gradual epithelialization and formation of a hairless atrophic scar . Small bony defects tend to close spontaneously during infancy. Large or multiple scalp defects may require surgical intervention.
The management of ophthalmological problems in AOS does not differ significantly from those who do not have this syndrome, except for the increased risk for procedures under anesthesia due to the systemic abnormalities. The role of laser ablation of the avascular peripheral retina is unknown.
Aicardi Syndrome (MIM 304050)
Aicardi syndrome is characterized by the classic triad of, agenesis of the corpus callosum, distinctive chorioretinal lacunae, and infantile spasms. Aicardi Syndrome is an X-Linked dominant disorder. Invariably it occurs sporadically. It is seen only in females with in utero lethality in males. The severity of the clinical features appears to be related to the degree of X inactivation. Mosaic mutations have been suggested as possible cause for the rare phenotype of Aicardi that is seen in males. It may also be seen in males with 47 XXY Karyotype [34, 35]. A possibility that Aicardi syndrome is caused by new mutations on an autosome with gender-limited expression in females is currently being considered.
The presence of all three classic features is diagnostic for Aicardi syndrome. Some patients may not have all three characteristic features. The presence of at least two major features or additional features strongly suggests the possibility of Aicardi syndrome.
Agenesis of the corpus callosum,
Distinctive chorioretinal lacunae,
Other main features include
Cortical malformations (usually polymicrogyria)
Periventricular and subcortical heterotopia
Cysts around third ventricle and/or choroid plexus (typically not communicating with the ventricles)
Optic disc/nerve coloboma or hypoplasia
Supporting Features Include
Skeletal anomalies: vertebral and rib abnormalities
EEG which has characteristic asynchronous multifocal epileptiform abnormalities with burst suppression and dissociation between the two hemispheres (“Split-brain” EEG)
Gross asymmetry of the cerebral hemispheres
Vascular malformations or vascular malignancy
Aicardi syndrome incidence has been estimated to be 1:105,000 to 1:167,000 in the United States and slightly more common in some European countries .
The clinical picture is often dominated by neurological symptoms and signs. Other clinical findings include craniofacial, skeletal, gastrointestinal and dermatological manifestations. Some of these patients are at increased risk for certain tumors and cutaneous malignancies. Patients usually have significant neurologic compromise and developmental delay.
Aicardi suggested microcephaly, axial hypotonia, and appendicular hypertonia, hemiparesis and unilateral spasticity, global developmental delay and intellectual disability of varying severity as the main features of the syndrome [41–43]. Seizures dominate the neurological presentation. Seizures tend to develop in the first year of life and most by 3 months old. The seizures initially present as infantile spasms but with time present in different forms, often severe and refractory to medical management. Several neuroimaging findings have been reported. Corpus callosum agenesis is the most consistent and is one of the diagnostic criteria. The next consistent finding is polymicrogyria and cortical heterotopias. Polymicrogyria often involves the frontal and perisylvian regions. The heterotopias are almost always bilateral, asymmetric and most often involve the periventricular area [44, 45]. Opercular abnormalities include widening of the operculum and less commonly under development of the operculum. Intracranial cysts that typically do not communicate with the ventricular cavity are seen. The cyst walls show contrast enhancement on MRI. Posterior fossa abnormalities include superior foliar prominence of the vermis, inferior vermian hypoplasia, dysplastic or hypoplastic cerebellar hemispheres, cerebellar subcortical and/or periventricular heterotopias, enlarged cisterna magna and cerebellar cysts.
Dysmorphic Facial Features
Patients with Aicardi syndrome have characteristic craniofacial features which include posterior plagiocephaly, facial asymmetry , sparse eyebrows, large ears, prominent premaxilla, short philtrum and upturned nasal tip. Some of the patients have cleft lip and palate.
Costovertebral abnormalities are common including hemi-, block, and fused vertebrae. Missing ribs are common. Scoliosis is seen in almost one third of the affected individuals .
Diarrhea, constipation, Gastroesophageal refluxes are commonly reported symptoms.
Chorioretinal lacunae are required for the diagnosis of Aicardi syndrome. This clinical finding is highly specific but not pathognomonic. They are usually found in the peripapillary retina or macula. The lesions are white or yellow-white colored, well-circumscribed, round, depigmented areas of the retinal pigment epithelium and underlying choroid. The borders of the lesion often have variable pigmentation. Donnenfeld et al. reported several ophthalmic manifestations including microphthalmia, optic nerve coloboma often usually without co-existent iris coloboma, nystagmus and retinal detachment . Within lacunae, the RPE is typically absent, and the choroid and sclera are thin . The reported eye findings can be unilateral or bilateral and can be grossly asymmetric. Other optic nerve abnormalities include optic nerve aplasia and hypoplasia . Patients also often have cortical visual impairment.
Diagnosis is based on the diagnostic criteria. Any female infant with seizures early in life needs to have an eye examination to rule-out Aicardi syndrome. Currently there is no specific laboratory, DNA test or diagnostic imaging test to establish a definitive diagnosis. Some of the findings that occur in Aicardi syndrome can also occur in isolation such as agenesis of the corpus callosum and infantile spasm. Parenchymal abnormalities may also be seen in neuronal migration disorders. Some features may share overap with Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) (OMIM 152950).
Presence of features like agenesis of the corpus callosum with intracranial cysts and other brain abnormalities in a female infant during prenatal ultrasound examination should raise the suspicion for possible Aicardi syndrome. Early ophthalmic fundus examination is critical in all female children with medically refractory seizures to make the correct diagnosis and differentiate it from other causes of seizures in female children and infants.
Infantile spasms are often difficult to manage and may be most responsive to vigabatrin. To monitor the side effects of vigabatrin, electroretinogram especially the 30-Hz flicker ERG provides assessment of retinal damage and Ocular Coherence tomography is often required .
No specific treatment is possible for the chorio-retinal lacunae.
Alagille Syndrome (AGS; MIM 118450)
Alagille syndrome (AGS; OMIM 118450) is a complex multisystem disorder involving predominantly the liver, heart, eyes, face, and skeleton . It is inherited as an autosomal dominant condition. It is also referred to as Arterohepatic dysplasia.
The diagnosis of AGS is based on clinical criteria initially set forth by Alagille et al. . Which include the histological finding of bile duct paucity on liver biopsy in association with three out of five major clinical features (cholestasis, cardiac defects, vertebral anomalies, ophthalmologic findings, and facial features) and is referred as the classic clinical criteria. Since the association of butterfly vertebrae and cardiac anomalies can be seen in other conditions like chromosome 22q deletion , a revised diagnostic criterion has been recently proposed by Kamath et al. . They included presence of typical renal anomaly (renal dysplasia, acidosis, vesico-ureteric reflux and urinary obstruction) as the sixth disease defining criteria.
The majority of cases (97 %) are caused by haploinsufficiency of JAG1 at 20p11.2-20p12 which encodes the protein (JAGGED1). JAG1 gene has not been implicated in any other phenotype. It consists of 26 exons, and encodes the JAGGED1 cell surface protein that functions as a ligand for the Notch receptors. There are four receptors Notch 1, 2, 3, and 4. These receptors act as transmembrane proteins, and interaction with their ligands triggers a cascade of intracellular downstream effects that result in transcription of genes. These subsequently help determine cell fate and differentiation. Most of the mutations that involve JAG1 are protein-truncating. No specific hotspots have been identified, and any part of the entire coding region may be involved. Gene deletions are found in less than 10 % cases. Larger deletions are likely to be associated with additional problems such as learning difficulties. New mutations occur commonly (60 %), and the rate of germline mosaicism may also be relatively high. A small percentage (1 %) is caused by mutations in NOTCH2 , in which group renal malformations may be more common. Both genes are components of the Notch signaling pathway. NOTCH2 gene comprises of 34 exons and encodes the NOTCH2 transmembrane protein. De novo mutations contribute to approximately 60 %. Germline mosaicism may occur at a frequency up to 8 % . The current consensus is that AGS is possibly due to a vasculopathy. This is supported by the spectrum of vascular anomalies seen in AGS. There is also evidence that the formation of mature tubular bile ducts follows on from the initial development of the intrahepatic arterial network accounting for the biliary duct atresia .
A characteristic inverted triangular face (broad, prominent forehead; pointed chin; bulbous tip of the nose; and deep set, hyperteloric eyes), posterior embryotoxon, cardiovascular defects (particularly peripheral pulmonary artery hypoplasia), and skeletal abnormalities (butterfly vertebrae, shortened ulna and distal phalanges) constitute the main clinical features [57–59].
Recognizing the dysmorphic facial features is critical and one of the major criteria for making a diagnosis . Alagille et al. determined the facial phenotype to be present in 95 % of cases in his series . This was supported in a subsequent study by Emerick et al. who found the characteristic facial phenotype in 96 % of 92 patients . The characteristic facial features include a prominent forehead, deep-set eyes that may be hyperteloric, straight nose with a flattened tip, and prominent pointed chin.
Sokol et al. suggested that the facial dysmorphism seen in AGS was nonspecific and was secondary to a variety of causes resulting in congenital intrahepatic cholestasis . They referred it to as “cholestasis facies” They suggested that a common structural effect involving several disease genes or the effect of the multiple biochemical aberrations caused by the cholestasis resulted in the facial phenotype. Kamath et al. in their series found that the facial phenotype had 76 % sensitivity and 85 % specificity in making a diagnosis of Alagille syndrome suggesting that the facies seen in Alagille syndrome was very specific to this condition . Hence recognition of the facial features is considered a significant clinical finding and is frequently integral to making the correct diagnosis.
The facial features are more difficult to recognize in adult patients, although recognition of this phenotype in adults has major clinical implications. Individuals might have been followed for apparently isolated congenital heart disease but may be at risk for having severely affected children with full clinical manifestations. The recurrence risk of congenital cardiac abnormalities in children of adults with truly isolated cardiac defects is generally less than 5 % but this risk rises to 50 % in Alagille syndrome .
Paucity of bile ducts, which is a histological diagnosis from liver biopsy, occurs in a diverse group of conditions, which, apart from AGS, include Down syndrome, cystic fibrosis, congenital infections, alpha-1-antitrypsin deficiency, and Zellweger and Ivemark syndromes . Screening for characteristic ocular findings may allow early diagnosis and differentiate Alagille syndrome from other causes of intrahepatic cholestasis thus avoiding the need for the extensive and invasive systemic investigations.
Chronic cholestasis occurs in a very high proportion (95 %) of patients . It often manifests in the first 3 months of life, with jaundice due to conjugated hyperbilirubinaemia. Progressive liver disease eventually resulting in cirrhosis and liver failure require a liver transplantation in approximately 15 % of cases. However a very small proportion of patients do not develop liver disease .
More than 90 % have a cardiac abnormality. Involvement of the pulmonary outflow tract in the form of peripheral pulmonic stenosis is the most common finding. Tetralogy of Fallot (TOF ) is the most common complex structural anomaly. Congenital heart disease may sometimes be the only manifestation of a mutation in JAG1 .
A characteristic form of segmentation anomaly known as ‘butterfly’ vertebrae occurs due to failure of fusion of the anterior vertebral arches. This finding is seen in at least 80 % of cases. These do not have any functional significance but help in making a diagnosis of Alagille syndrome in a child with cardiac disease. Craniosynostosis and radioulnar synostosis have also been reported . Other vertebral anomalies including spina bifida occulta and fusion of adjacent vertebrae, hemi vertebrae, and absence of the 12th rib has been reported. Digits may have shortening of the distal phalanges resulting in fusiform appearance of fingers.
Several vascular abnormalities have been reported. Neurovascular accidents, , renovascular anomalies, aortic syndrome, and moyamoya syndrome [65, 66] have been reported. Anomalies of the major intracranial blood vessels involving the basilar, carotid, and middle cerebral arteries have also been reported [64, 67]. Intracranial bleeding may occur following trivial head trauma.
They contribute to a significant cause of mortality.
Structural renal abnormalities include renal dysplasia, small kidneys, renal cysts, and ureter pelvic obstructions. Renal tubular acidosis is the most common functional abnormality reported . Cardiac disease, when severe, accounts for early mortality, whereas hepatic complications account for a significant proportion of later deaths.
Growth retardation and learning difficulties have been reported.
The most consistent ocular finding is posterior embryotoxon. Other reported anterior segment abnormalities include microcornea, nanophthalmos, keratoconus, band keratopathy, corneal pannus, iris hypoplasia, corectopia, and cataract [68–74, 76, 77]. Refractive errors and strabismus have also been reported [69, 70]. Posterior segment abnormalities include disc and retinal vascular abnormalities [75, 76]. Several optic disc anomalies including tilting, hypoplasia, elevation, atrophy, temporal crescent, peripapillary depigmentation may occur. Optic disc drusen are extremely common and ocular ultrasound has been suggested as a possible noninvasive, simple, and safe method for diagnosis in infants with cholestatic jaundice . Retinal vascular and pigmentary changes, with macular pigment clumping, speckling and chorioretinal folds can occur .
Ophthalmic findings are usually mild and most are non-progressive. Hence most patients tend to have reasonably good vision .
Molecular genetic testing is currently available, although, mutations may not be detected either in JAG1 and NOTCH2 in a proportion of the patients.
Alagille must be differentiated from other causes of intrahepatic cholestasis such as cystic fibrosis, congenital infections, alpha-1-antitrypsin deficiency, Zellweger syndrome and Ivemark syndromes . Alagille has a relatively better prognosis for liver disease. The characteristic dysmorphic features, classic ocular findings and specific cardiac abnormalities are not seen in the remaining clinical conditions. Hence it is imperative to look for these findings in any child with neonatal cholestatic jaundice. Several reports suggest examination of the parents alone might provide the diagnosis in at least 36–43 % of cases, and simple ocular examination of the child could reveal a characteristic abnormality in most patients. However posterior embryotoxon is present in 8–15 % of normal persons .
Multiple specialty services are usually involved. The Kasai procedure, an direct intestine-hepatic anastomosis, is the most common surgical approach to the live malfunction.
The retinal pigmentary changes usually do not affect vision.
Alstrom Syndrome (ALMS MIM 203800)
Alström syndrome is an autosomal recessive genetic disorder characterized by cone-rod dystrophy, hearing loss, childhood truncal obesity, insulin resistance and hyperinsulinemia, type 2 diabetes, hypertriglyceridemia, short stature in adulthood, cardiomyopathy, and progressive pulmonary, hepatic, and renal dysfunction. Symptoms begin to appear even during early infancy and the progressive development of multi-organ pathology results in reduced life expectancy. Though this disorder is unusually frequent among French Acadians, it also occurs in other ethnic groups.
Alström syndrome is caused by bilalellic mutations in the ALMS1 gene OMIM 203800, located on chromosome 2p13. ALMS1 is expressed in the organ of Corti, retinal photoreceptors, renal tubules, liver, and pancreatic islets [80, 81]. Several splice variants of ALMS1 have been described encoding isoforms of the protein accounting for high variability in severity of tissue involvement. Onset of retinal degeneration before age 1 year and occurrence of urologic dysfunction have been linked with disease-causing variants in exon 16 . A more significant association was also found between alterations in exon 8 and absent, mild, or delayed renal disease. There is great variability in age of onset and severity of clinical symptoms, even within family members bearing identical mutations.
The Marshall criteria describe eight major and eight minor clinical features . The recent revised criteria are shown in Table 21.1 . The disorder appears to segregate into three groups: Less than 2 years old, 3–14 years and above 15 years. Presence of two major features is sufficient to make the diagnosis in the first two groups. If only one major criterion is present, the number of additional minor criteria required to make the diagnosis increases with each subsequent age group (2 in group 1, 3 in group 2 and 4 in group 3). The major criteria remain the same for the three age groups. The minor criteria differ in each age group as more systems tend to get affected with disease progression.
Alstrom syndrome : diagnostic criteria and clincial features
Major criteria (same for all age groups)
Presence of ALMS1 mutation in one allele and/or
Family History of Alstrom Syndrome
Vision related issues (photophobia/nystagmus/reduced visual acuity/cone dystrophy confirmed by an ERG/legal blindness in adults)
Birth to 2 years
Dilated Cardiomyopathy/Congestive Heart failure
3 years–14 years
Obesity and/or insulin resistance and/or T2 DM
History of dilated cardio myopathy/congestive heart failure
Hepatic dysfunction and renal failure
Advanced bone age
15 years and above
Findings under minor criteria mentioned for age group 3–14 years
Additional findings include:
Females: irregular menses and/or hyperandrogenism
Supportive findings (common to all age groups)
Recurrent pulmonary and urinary tract infections.
Hyperlipidemia, scoliosis, flat feet, hypertension, hypothyroidism, recurrent UTI and alopecia (15 years and above)
It was first described by Alström in 1959.
Alström syndrome appears to have a prevalence of less than one per million in the general population . Patients usually have worsening of all symptoms and signs by second/third decade resulting in reduced life expectancy due to progressive multisystem involvement.
Obesity is one of the early and consistent findings observed in most children with Alström syndrome. They have apparently normal birth weight but gain weight rapidly within the first or second year of life. Decreased levels of physical activity, often exacerbated by dual neurosensory losses and childhood hyperphagia contribute.
Sensorineural Hearing Loss
Hearing loss may be detected in early infancy. It is bilateral and progressive. Most patients have moderate to severe hearing impairment by the second decade . The age of onset and severity is highly variable. Chronic and acute otitis media often exacerbate the sensorineural deficits with a component of conductive hearing loss .
Both dilated cardiomyopathy and restrictive cardiomyopathy has been observed [83, 86]. Dilated cardiomyopathy is more common in early infancy and childhood. It may be the presenting sign of the syndrome. Most children recover but can have a recurrence in later childhood when it presents as restrictive cardiomyopathy. Sixty percent of children with cardiomyopathy develop congestive cardiac failure.
Chronic bronchitis, asthma, and chronic rhinosinusitis are common. Pulmonary hypertension, Chronic Obstructive Pulmonary Disease and Adult Respiratory Distress Syndrome also occur. History of recurrent hospitalizations for breathlessness is common as some individuals are unable to maintain adequate oxygen saturation.
Type II Diabetes Mellitus
Severe insulin resistance, hyperinsulinemia, and impaired glucose tolerance are often observed from very early childhood. Acanthosis nigricans, a marker of insulin resistance, may occur. The onset of Type II Diabetes Mellitus has been shown to be unrelated to the degree of obesity, unlike the general population .
Elevation of transaminases is common and is often the initial finding. In patients with severe involvement, cirrhosis, portal hypertension, esophageal varices, encephalopathy, with upper gastrointestinal hemorrhage may result in death. End stage liver disease is the cause of death in approximately 10% of individuals .
Renal abnormalities include reduced urine concentrating ability, renal tubular acidosis, polyuria and polydipsia. Secondary hypertencion may occur. Lower urinary tract dysfunction, vesicoureteral reflux, urethral stenosis, and detrusor instability due to abnormal bladder and sphincter function have also been reported .
Hyper- or hypogonadotropic hypogonadism is seen in both males and females. It is more common in males. Secondary sex characteristics are normal. Affected females tend to have hyperandrogenism, hirsutism, and alopecia. No individuals with Alström syndrome are known to have reproduced.
Mild delay in developmental milestones, autistic spectrum behaviors, seizures, and cerebellar anomalies can occur.
Progressive cone-rod dystrophy is the main clinical feature. It usually begins in early infancy with parents noticing photophobia, visual impairment and high frequency small amplitude symmetric nystagmus due to early involvement of cones. Full Field-ERG is required to confirm the diagnosis to demonstrate the early cone involvement. When rods get subsequently involved, there is progressive deterioration of vision, constriction of visual fields and eventual blindness usually by third decade. Posterior subcapsular cataracts have been reported. Retinal findings include attenuation of retinal vessels, optic disc pallor, optic nerve drusen and increasingly significant retinal pigmentary epithelial (RPE) atrophy . Histological studies have demonstrated other findings including asteroid hyalosis [91, 92]. The retina may eventually appear as advanced retinitis puigmentosa. Reports have showed thinning of the macula and an early arrest of macular development with immature retinal structural organization in one of the patients . The severity and age of onset of the retinal degeneration vary among affected individuals .
Molecular genetic testing is available and is one of the major criteria for making a diagnosis.
Since Alström syndrome causes a severe retinal dystrophy with reduced vision and photophobia, it could be confused with several early onset pediatric retinal dystrophies. These include Leber congenital amaurosis (LCA ), cone dystrophy and achromatopsia. Often an initial diagnosis of achromatopsia is revised as further characteristic systemic findings emerge. The absence of obesity and other systemic abnormalities, presence of oculodigital sign, enophthalmos and an extinguished ERG response are seen in LCA .
The phenotypic characteristics of Alström syndrome also resemble Bardet-Beidl syndrome (BBS) BBS has polydactyly which is not seen in Alström syndrome. Hearing impairment is less common with BBS. Obesity , insulin resistance and diabetes are common findings in both disorders tend to present slightly at a later age than Alstrom syndrome. Intellectual disability and hypogonadism are more common in BBS.
Other differential diagnoses include Wolfram, Cohen, Biemond II and Usher syndromes. Cohen syndrome has long tapering fingers, a classic facial appearance and high myopia. The presence of diabetes insipidus in addition to diabetes mellitus suggests Wolfram syndrome (also known as DIDMOAD syndrome). The macula is normal in DIDMOAD syndrome . The presence of iris coloboma suggests Biemond syndrome. Obesity is not a feature of Usher syndrome and most of the systemic findings seen in Alstrom syndrome are absent in Usher syndrome. Vestibular abnormalities, as seen in Type 2 Usher syndrome but do not occur in Alström.
Correction of refractive error and vision rehabilitation is required. Given the poor prognosis for vision, early intervention is required. Patients should be screened periodically by echocardiogram to result out emerging cardiomyopathy. Prescription of tinted glasses to avoid photophobia can be attempted. Recommended health care guidelines include
Height, weight and BMI
Fasting Blood sugar
Serum lipid profile
Renal function tests
Liver function tests
Cardiac evaluation by pediatric cardiologist
Systemic geneticist consult
Axenfeld-Reiger Spectrum (ARS MIM 180500)
Axenfeld–Rieger syndrome (ARS) is an autosomal dominant disorder, characterized by anterior segment dysgenesis, dysmorphic facial features and systemic developmental abnormalities. ARS is most often caused by mutations of either FOXC1 (601090) and PITX2 (601540). Other genes that have been implicated to have a possible role include GJA1 . These encode transcription factors which play a critical role in the development of the anterior segment of the eye. The timing of expression and dosage of these transcription factors is critical . Gain of function or haploinsufficiency can result in similar phenotypes [87, 97, 98]. Patients with mutations in PITX2 are more likely to have systemic abnormalities. An anirdicphenotype can result from 6p25 dosage abnormalities.
The clinical condition had been described earlier as several forms initially separated as Axenfeld anomaly, Axenfeld syndrome, Rieger anomaly and Rieger syndrome. It has since been recognized that these phenotypes all fall in a continuum, currently referred as Axenfeld-Rieger spectrum. Axenfeld described posterior embryotoxon with attached iris strands in 1920 . Rieger anomaly was first described by Austrian ophthalmologist, Herweh Rieger, in 1935 [100, 101].
Axenfeld-Rieger spectrum has an estimated prevalence of 1 in 200,000 people .
Dysmorphic Facial Features
The facies is characterized by subtle craniofacial dysmorphism which includes prominent forehead, broad and flat nasal bridge, mid-facial abnormalities maxillary hypoplasia, hypertelorism and telecanthus.
Absent teeth, microdontia, delayed eruption, cone shaped teeth and increased spacing between teeth may be seen.
Redundant Periumbilical Skin
Failure of involution of the periumbilical skin in the abdominal region leads to the typical “elephant trunk” umbilicus. Patients also have an increased incidence of umbilical hernia.
Hypospadias in males, pituitary abnormalities, growth retardation and anal stenosis may be observed .
Prominent anteriorly displaced Schwalbe line (the peripheral termination of Descemet’s membrane and the anterior limit of the trabeculum) is referred to as posterior embryotoxon . It is seen in 15 % of normal population . It is one of the most consistent findings but not essential to make the diagnosis of ARS. However in the presence of posterior embryotoxon in a child with anterior segment dysgenesis and glaucoma, one should first consider ARS.
Abnormalities of the Iris
Several iris abnormalities can be observed including iris hypoplasia, correctopia and polycoria and most uncommonly, anirdia [106, 107]. Iris processes to the posterior embryotoxonmay or may not be present. Patients with aniridia phenotype do not have the other panocular features of aniridia due to PAX6 mutation and are not at risk for Wilms tumor.
There are no specific diagnostic criteria. If systemic features apart from those discussed above occur, a chromosomal abnormality involving these genes should be suspected or alternative diagnosis considered. Peters anomaly, ICE (Irido-Corneal-Endothelial) syndrome, aniridia, congenital ectropion uveae and ectopia lentis etpupillae may mimic ARS. Peter’s anomaly is characterized by corneal opacification and variable degrees of irido- or lenticulo-corneal touch. ICE is unilateral and not found in early childhood. True anirdia is associated with foveal hypoplasia, corneal pannus, nystagmus and cataract. Congenital ectropion uveae is unilateral and characterized by prominent ectriopian uvea and a whitish tissue on the iris surface. Ectopia lentis etpupillae has no posterior embryotoxon but also has ectopia lentis in a direction opposite of the corectopia. It may be seen by slit lamp biomicroscopy but gonioscopy is required to detect it in subtle cases . Clinical genetic testing is available. Chromosomal microarray can be useful in identifying the etiology of anirdia like phenotype in such patients in addition to the clinical differentiation discussed.
Management : Recommendations
Hearing assessment, systemic genetics consult, dentist consult are required.
Patients with ARS have a life time risk of glaucoma and should be monitored. If glaucoma requires surgery, the angle anatomy may make trabeculotomy or goniotomy difficult if not impossible. Periodic monitoring of IOP and disc is critical in all patients with ARS as they have a life time risk of developing glaucoma.
Bardet-Beidl Syndrome (BBS)
Bardet-Biedl syndrome is an autosomal recessive genetically heterogeneous ciliopathy characterized by retinitis pigmentosa, obesity, renal dysfunction, polydactyly, developmental delay, and hypogonadism. It is one of the more common forms of syndromic RP. It shows very high interfamily and intrafamilial variability. Like most other autosomal recessive disorders, it is more common in highly consanguinous population. It is the first clinical condition where triallelic inheritance characterized by the requirement of 3 mutations in 2 genes to manifest the disease, has been demonstrated.
Bardet-Biedl syndrome can result from mutations in at least 14 different genes. These genes play a critical role in the structure and normal functioning of cilia. BBS1 accounts for most cases of BBS. BBS10 is the second most common gene involved. The product of eight genes implicated in the disorder, assemble to form a stable complex called the BBSome . This plays a critical role in signalling receptor trafficking to and from the cilia. Defects in any of the BBS genes eventually affects this complex resulting in ciliopathy and hence BBS. Patient with mutations in BBS1 tend to be taller . Heterozygous carriers have been shown to have increased risk of obesity, hypertension, diabetes mellitus, renal disease and adenocarcinoma [111, 112].
The disorder was previously grouped as one entity along with Lawrence-Moon syndrome as Lawrence-Moon-Bardet-Beidl Syndrome . The first case was reported by Laurence and Moon in 1866. Laurence–Moon syndrome is usually considered a separate entity. Laurence-Moon syndrome is a distinct disorder characterized by the presence of paraplegia and absence of obesity and polydactyly .
The estimated incidence is approximately 1:160,000 in northern European populations and 1:13,500 in some Arab populations .
Dysmorphic Facial Features
The facial features are often subtle and inconsistent: deeply set eyes, hypertelorism, down-slanting palpebral fissures, depressed nasal bridge, small mouth, malar flattening, and retrognathia. Minimal cranial dysmorphic features include brachycephaly, macrocephaly and male frontal balding.
Polydactyly is seen in approximately 60–80 % of patients [115, 116]. Polydactyly is post-axial and can be seen in upper and/or lower limbs (see Fig. 21.2a–c). It might vary in severity from a small bump to a large complete finger. Other digital anomalies include syndactyly, brachydactyly, and clinodactyly and “sandal-gap” in toes.
(a) Surgical scars following removal of supernumerary post axial polydactyly. (b) Photograph of another patient with polydactyly of the foot. (c) Photograph of another child with polydactyly (Photo courtesy Dr. P. Vijayalakshmi, Aravind Eye Care System, Madura)
Patients with BBS usually have normal birth weight . The obesity is truncal in nature and acquired over time. Most patients are obese and often also have associated endocrinological abnormalities. Insulin resistance can be observed and acanthosis nigricans might be seen. Factors contributing to obesity include increased food intake, decreased energy expenditure, reduced physical activity and increased peripheral leptin resistance .
Hypogonadotropic gonadism is more common in males than in females.
Cryptorchidism and micropenis may also occur. Complex structural urogenital abnormalities can occur in females including partial and complete vaginal atresia, septate vagina, duplication of the uterus, hematocolpos, persistent urogenital sinus, vesico-vaginal fistula, absent vaginal orifice, and absent urethral orifice [118–120]. Hypoplastic fallopian tubes , uterus and ovaries can also occur.
Developmental delay, speech delay, behavioral abnormalities, brachydactyly, syndactyly, ataxia, diabetes, cardiovascular anomalies, hepatic fibrosis, Hirschsprung disease and anosmia have been reported .
The primary feature is retinal dystrophy. Although it is usually rod-cone, cone-rod phenotypes have also been reported and macular lesions are not uncommon . Retinal dystrophy is observed in 90 % of patients. It usually begins in late childhood and shows typical features of retinitis pigmentosa, but may initially only manifest as internal limiting membrane irregularity and attenuated vessels. Night blindness is the earliest symptom, beginning usually at 7–8 years of age. It is followed by slowly progressive visual field loss. The maculopathy may or may not be associated with peripheral retinal degeneration. There is high inter-familial variability in the onset and severity of symptoms. Other ophthalmic findings include secondary nystagmus, cataract and strabismus as well as primary refractive errors, mainly myopia and astigmatism. Glaucoma is rarely seen .
A diagnosis can be made based on the presence of four primary clinical features or a combination of three primary features and two secondary features .
The primary features include rod-cone dystrophy, polydactyly, truncal obesity, learning disability, hypogonadism and renal anomalies.
The secondary features include developmental delay, speech delay, behavioral abnormalities, and ocular manifestations other than retinal dystrophy like cataract, strabismus and refractive errors, ataxia, hypertonia, endocrine abnormalities like diabetes, cardiac, orodental anomalies and hepatic disease. Hirschsprung disease and anosmia are other secondary features.
Molecular genetic testing can confirm the diagnosis and microarray panel technology for genes known to be involved in BBS is available. There are several clinical conditions which resemble BBS. It is important to carefully observe for surgical scars as many patients would have had a surgical excision at a very young age for cosmetic reasons (see Fig. 21.2a). In the absence of polydactyly it is often difficult to differentiate BBS from many other clinical conditions. However onset of ocular features assists in distinguishing from other clinical conditions. Many patients reported in the literature who were initially diagnosed to have McKusick Kaufmann syndrome were later diagnosed to have BBS when retinal dystrophy became evident. It is currently recommended that all children with a possible diagnosis of McKusick-Kaufman syndrome made during infancy should be re-evaluated for ophthalmological findings and other signs of BBS during follow-up .
McKusick-Kauffman Syndrome (MKS)
It is characterized by the triad of hydrometrocolpos, postaxial polydactyly, and congenital heart disease. It is caused by mutation of MKKS, which can also cause BBS accounting for the similar clinical features. MKS is also inherited in an autosomal recessive manner. The main differentiating feature is the absence of retinal dystrophy in MKS.
Meckel-Gruber syndrome , another autosomal recessive condition is usually lethal. It consists of the triad of occipital encephalocele, large polycystic kidneys, and postaxial polydactyly. It is associated with other anomalies that include genital anomalies, central nervous system malformations, and fibrosis of the liver. Pulmonary hypoplasia is the most common cause of death. Mutations in MKS1 and TMEM67 can also cause Bardet-Biedl syndrome, thereby demonstrating phenotypic overlap between these two conditions [126, 127].
Alström Syndrome (See Above)
The presence of ocular coloboma in a child with features with BBS should alert the clinician to this diagnosis. Hydrocephalus and facial dyostosis are additional features.
This autosomal recessive inherited disorder is characteristised by facial dysmorphism, truncal obesity and retinal dystrophy. There is no polydactyly but the fingers are long and tapering. Some patients also have hyperextensibility of joints. Cerebellar involvement is common and revealed by neuro-imaging. The retinal dystrophy is also different from BBS, and more characterized by pathologic myopia. Transient neutropenia is seen. Intellectual disability tends to be less severe than in BBS. Microcephaly is also a feature.
Management : Recommendations
Renal function tests including blood urea and serum creatinine, ultrasound abdomen and pelvis to detect renal and urogenital anomalies is advised. Blood pressure and periodic weight measurement and monitoring should be performed. Developmental assessment, endocrinological evaluation and hearing assessment should be performed. Polydactyly might also cause not only cosmetic concerns but can also cause significant functional limitations in some patients including writing. Pre-axial polydactyly can occur as an isolated genetic disorder or can be seen in other genetic syndromes but is not seen in BBS.
Although there is currently no specific treatment for the retinal dystrophy in BBS, a gene therapy trial for one genotype is expected in the near future.
Blepharophimosis Syndrome (BPes MIM 110100)
Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES; OMIM 110100) is an autosomal dominant syndrome characterized by the presence of four adnexal features: shortened horizontal palpebral fissure length, ptosis, epicanthus inversus, and telecanthus . It has two subtypes. Type I is characterized by the additional finding of primary ovarian failure in affected females. Type 2 does not have ovarian failure. Mutations in the fork head transcription factor gene FOXL2 have been found to be responsible for BPES. There has been only one report of autosomal recessive transmission in an Indian family . Penetrance appears to be 100 % in BPES1 and 96.5 % in BPES2 . In BPES1 there is transmission by males only as females are infertile. In BPES2, transmission occurs through both sexes. Fifty percent of cases are due to de novo mutations. FOXL2 is the only gene currently known to be associated with BPES. A patient with BPES and genital malformations was reported to have a deletion del(7)(q34) . FOXL2 gene has a single exon and the encoded protein has an alanine-rich domain. Mutations predicted to result in proteins truncated before the polyalanine tract preferentially lead to BPES1.
Polyalanine expansions preferentially lead to BPES2. Positive correlation between the size of the polyalanine expansion and the penetrance of the BPES phenotype has been reported .
Occasionally individuals with BPES may have cytogenetic rearrangements, including interstitial deletions or translocations involving locus interface between 3q22.3 and 3q23  Waardenburg  suggested that the ocular defects seen in this syndrome possibly occurred during the third month of intrauterine life as this timing coincides with the critical period in the development of the ovary and the beginning of formation of the uterus by fusion of the Mullerian ducts. It has been shown in mice that the Foxl2 gene is expressed in the mesenchyme of developing mouse eyelids and adult ovarian follicles .
The exact frequency of BPES is unknown .
Apart from the primary ovarian failure seen in females affected with BPES1, there are no systemic findings. Secondary sexual characteristics in BPES1 are normal. Intellectual development is usually normal although mild intellectual disability has occasionally been reported and is usually present when a microdeletion is the cause. Large deletions often can cause other associated features like microcephaly, intellectual disability, and growth delay [138–141]. (Balanced translocations involving 3q23 lead to classic BPES without these additional findings.)
See Fig. 21.3.
This female child has ptosis, epicanthus inversus, telecanthus and blepharophimosis, the characteristic features of BPES (Photo courtesy Dr. P. Vijayalakshmi, Aravind Eye Care System, Madurai)
Shortened Horizontal Palpebral Fissure Length
The horizontal palpebral fissure length in individuals with BPES usually measures less than 20 mm.
Ptosis is usually severe with poor levator function and present at birth. Patients might use their frontalis muscle in an attempt lift the drooping lid or adopt a compensatory chin up posture. Though the ptosis can cause stimulus deprivation amblyopia or uncorrected refractive error and anisometropia may also contribute .
Telecanthus has been reported as the most consistent finding of the syndrome . It is characterized by lateral displacement of the inner canthi with normal interpupillary distance. It may or may not be associated with hypertelorism.
BPES is characterized by the presence of epicanthus inversus, where the lower lid contributes to most of the epicanthus and the epicanthal fold extends onto the lower lid below the lashes. Unlike other types of epicanthus, epicanthus inversus does not improve much with age.
Other Eye Abnormalities
Congenital nasolacrimal duct obstruction and strabismus also have a higher incidence in BPES . Hypoplastic supraorbital rims, bushy eyebrows, low set ears and broad nasal bridge are other reported findings particularly in patients with deletions. There is often lateral displacement of the upper and lower lacrimal puncta, more than what would be expected from the lateral displacement of the inner canthi alone .
BPES is a clinical diagnosis. Molecular genetic testing is currently available.
Chromosomal microarray may be indicated when non ocular features, in particular developmental delay, other than ovarian failure are present. In girls, a positive family history of BPES and infertility can indicate the type of BPES. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in the family has been identified. There are many syndromes which have either ptosis or blepharophimosis as a feature. In particular, Ohdo syndrome is an X-linked recessive disorder with blepharophimosis, developmental delay and a characteristic facies. Say-Barber syndrome has blepharophimosis, developmental delay, thyroid dysfunction and dental anomalies.,
There is no specific treatment for the primary ovarian failure and infertility in BPES1. Hormone replacement therapy and other reproductive assisted options are available.
Females with BPES should be evaluated for primary ovarian failure.
The usual approach to this condition is surgical. Medial canthoplasty, for example the Roveda procedure, is often done first at which time correction of the epicanthus may also be accomplished. Ptosis surgery is sometimes performed as the last procedur unless earlier intervention for amblyopia is needed. Levator sling operations tend to be the procedure of choice. The last phase of the correction is usually the extension of the lateral canthus.
CHARGE Syndrome (MIM 214800)
CHARGE syndrome is the mnemonic for Coloboma , Heart anomaly, Choanal Atresia, Retardation of growth and/or development, Genital and/or urinary anomalies and Ear Anomalies and deafness. Not all features need to be present .
The diagnostic criteria as described by Blake et al. (1998), which was modified by Amiel et al. (2001) and subsequently by Verloes (2005) is shown in Table 21.2 [144–146]. The major diagnostic characteristics of CHARGE syndrome are the following.
CHARGE syndrome : diagnostic criteria and clincial features
Coloboma of the iris, retina, choroid, disc; microphthalmia
Cranial nerve dysfunction or anomaly
I: hyposmia or anosmia
VII: facial palsy (unilateral or bilateral)
VIII: hypoplasia of auditory nerve
IX/X: swallowing problems with aspiration
Choanal atresia or stenosis
Unilateral/bilateral: bony or membranous atresia/stenosis
CHARGE syndrome ear
External ear anomalies including “snipped off” helix, prominent antihelix that is usually discontinuous with tragus, triangular concha, decreased cartilage.
Middle ear: ossicular malformations
Mondini defect of the cochlea
Temporal bone abnormalities, absent or hypoplastic semicircular canals
Dysmorphic facial features
Square face with broad prominent forehead, prominent nasal bridge and columella and a flat midface
Micropenis, cryptorchidism in Males
Males and females: delayed puberty secondary to hypogonadotropic hypogonadism
Short stature, with or without growth hormone deficiency
Delayed milestones, hypotonia
Tetralogy of Fallot, AV canal defects, and aortic arch anomalies
Cleft lip and/or palate
DiGeorge sequence, Omphalocele or umbilical hernia, bony scoliosis or Hemivertebrae, Renal anomalies including dysgenesis, horseshoe/ectopic kidney, hand anomalies including polydactyly, altered palmar flexion creases, atypical split hand/split foot deformity, short webbed neck, sloping shoulders, and nipple anomalies
Typical CHARGE syndrome
4 Major criteria or 3 Major + 3 Minor
Probable/possible CHARGE syndrome
One or two major + several minor features
The presence of four major criteria or a combination of three major and three minor criteria is required. The major features are specific to this syndrome while the minor features are not specific and can be observed in other clinical conditions.
CHARGE syndrome is most often caused by heterozygous mutations in the CDH7 gene . Most patients have denovo mutations . Increased paternal age appears to be risk factor . Genetic testing is available on a clinical basis. The gene encodes the chromodomain helicase DNA-binding protein which is essential for the formation of multipotent migratory neural crest cells which subsequently undergo a major transcriptional reprogramming and acquire a broad differentiation potential. These then migrate throughout the body, giving rise to various important structures that include craniofacial bones and cartilages, the peripheral nervous system and cardiac structures .
CHARGE syndrome occurs in approximately 1 in 8500 to 10,000 individuals .
Dysmorphic Facial Features
CHARGE syndrome is characterized by a square face, flat midface, broad prominent forehead, and prominent nasal bridge and columella.
Congenital malformations of the heart are seen in 75–85 % of patients. Many forms of congenital cardiac anomalies can occur.
Observed in up to 60 % of patients, the choanal atresia may be membranous or bony, unilateral or bilateral. Bilateral choanal atresia presents as an emergency at birth with acute respiratory distress. Unilateral atresia may present as unilateral rhinorrhea. Choanal stenosis may also be an incomplete manifestation.
Retarded Growth and Development
Growth retardation and developmental delays commonly occur. Feeding difficulties due to coexistent congenital malformations such as orofacial clefts and tracheoesophageal fistula contribute to growth retardation. Both pre- and post-natal growth deficiency is observed, but patients usually have normal birth weight and length.
Cryptorchidism is seen in males and hypogonadotropic hypogonadism occurs in both males and females. Solitary kidney, hydronephrosis, and renal hypoplasia are some of the renal anomalies. They occur in approximately 25–40 % of children .
Ear Anomalies and Hearing
At least 80 % of patients have some form of ear anomaly. The abnormalities can involve the inner ear, middle ear and/or outer ear. The external ear is usually short and wide. The ear lobe may be absent. There is a prominent antihelix that is often discontinuous with the tragus, truncated helix and triangular concha. The middle ear may show ossicular malformations. The semicircular canals may be hypoplastic or absent. Mondini defect of the cochlea is a characteristic finding. The hearing loss can be sensorineural, conductive or mixed and can vary from a mild to profound hearing loss. The presence of facial palsy suggests the presence of hearing impairment .
Absence or hypoplasia of the semicircular canals can impair vestibular balance, especially when combined with visual loss.
Cranial Nerve Dysfunction
Hyposmia, unilateral or bilateral facial palsy, hypoplasia of the auditory nerve and problems with swallowing resulting in aspiration are the most common cranial nerve anomalies observed in CHARGE syndrome.
The hands may have a characteristic shape with broad palms and with a “hockey-stick” palmar crease, short fingers and small malformed thumbs.
Skeletal anomalies including scoliosis, rib, vertebral anomalies and limb anomalies, dental anomalies, global developmental delay, and gastro-esophageal reflux may be seen in these patients. Prognosis for life is guarded in the presence of bilateral choanal atresia, cardiac abnormalities and teacheo-oesophageal fistula or esophageal atresia . Male gender and central nervous system malformation appear to have adverse prognosis .
Coloboma may be unilateral or bilateral and seen in 80–90 % of the patients. There is often asymmetric involvement. Macular involvement results in poor visual prognosis. The coloboma may also involve the optic nerve or the optic nerve may be dysplastic. Eyes with coloboma are also prone to retinal detachment. The coloboma may involve only the iris or in some patients there might be a fundus coloboma in the absence of an iris coloboma. Microphthalmia when present further reduces the visual prognosis. Isolated iris coloboma does not affect visual acuity.
The diagnosis is said to be definitive if the patient has all four major criteria or three major and minor criteria each. The diagnosis is probable if the patient has one or two major and many minor criteria.
22q11.2 Deletion Syndrome
These children have a distinct facial dysmorphism very different from CHARGE syndrome. They also do not have the ear anomalies seen in CHARGE syndrome. Cleft palate in the absence of cleft lip is more common.
VACTERL association (Vertebral anomalies, Anal atresia, Cardiac anomalies, TracheoEsophageal fistula or esophageal atresia, Renal abnormalities and Limb anomalies) shares many minor features of CHARGE syndrome but lack the major clinical findings of CHARGE syndrome. Coloboma is absent.
Other differentials include Kabuki syndrome (distinct dysmorphic face, cleft palate,, persistent fetal fingertip pads) and renal-coloboma syndrome (also known as papillorenal syndrome , with its characteristic vacant optic disc) which has none of the other major features of CHARGE syndrome. The optic nerve “coloboma” seen in this syndrome is not due to failure of closure of the fetal fissure . Burn-McKeown syndrome (oculo-oto-facial dysplasia) is characterized by choanal atresia, hearing loss, cleft lip/palate, cardiac malformation and protruding ears but also has nasal deformity and lower lid coloboma rather than intraocular coloboma .
The extensive involvement of several systems requires a team management. Anesthesia considerations include the presence of choanal atresia, cleft lip and palate, and possibility of tracheomalacia.
A full dilated ophthalmologic examination by a pediatric ophthalmologist is required to determine the type and extent of the coloboma and to detect and treat refractive errors, strabismus and amblyopia. Cortical vision impairment (CVI) may contribute to the reduced visual acuity. Periodic follow-up examination to screen for retinal detachment is recommended.
Conradi Hünermann-Happle Syndrome: X Linked Dominant Chondrodysplasia Punctata (MIM 302960)
Chondrodysplasia punctata (CDP ) MIM 302960 is a clinically rare and genetically heterogeneous disorder which encompassesa group of several skeletal disorders characterized by the presence of abnormal foci of calcification at the epiphyseal plates, causing radiographic stippling. Cutaneous and ocular findings also occur.
The X-linked recessive from of CDP , known as CPDX1 is caused by mutations in the CPDX1 gene . Autosomal dominant and recessive forms also occur . Maternal vitamin K deficiency especially during early pregnancy and warfarin teratogenicity can cause CDP .
CPDX2 is inherited as an X-linked dominant disorder known as Conradi-Hünermann Happle syndrome and is the most well characterized form. Mutations in the gene encoding the emopamil-binding protein, encoded by the gene CPDX2 have been identified as an underlying cause. The syndrome occurs due to disturbances in the pathway of cholesterol biosynthesis. Increased levels of 8-dehydrocholesterol and 8-cholestenol are found in these patients. These metabolites appear to have a role on the hedgehog proteins and sonic hedgehog pathway. The Hedgehog proteins play a critical role in the development of limb buds and their correct orientation and also in regulating the embryonic patterning , Cartilage formation and enchondral growth.
Affected males usually die in-utero. Rarely males with a milder phenotype can be seen they have an additional X chromosome (e.g. XXY) . The gene is located at Xp11.22-p11.23. Variable inactivation of the X chromosome accounts for the variability in the ocular and systemic findings. Therefore, the phenotypic effect of a given mutation cannot be fully predicted. The hallmark of the condition is the punctate stippling of the epiphysis seen in radiographs in children [161, 162]. These findings tend to disappear after normal epiphyseal ossification in children. Hence early diagnosis is critical. Many clinical features resemble other X-linked dominantly inherited conditions.
The clinical features of CDPX2 were first described by Happle and hence referred to as Conradi-Hünermann-Happle (CHH) syndrome .
Malou et al. suggested that the incidence could be 1 in 5, 00,000 .
Dysmorphic Facial Features
Mild dysmorphic facial features including frontal bossing, saddle nose and hypertelorism are often observed. The scalp hair, eyebrows and eye lashes are scanty. Patches of cicatricial alopecia and twisted hairs also occur. The scalp hair also appears coarse and dry.
The most characteristic finding is calcific stippling of the epiphyses, particularly seen in the knees. It is most consistent in the first year of life and later disappears. Asymmetric shortening of limbs and bowing of the legs are prominent features. Scoliosis is frequent and can occur even in early infancy. Growth retardation and short stature are often present.
Icthysoiform eythroderma and collodion membrane formation can sometimes occur. During infancy, scaling and eythroderma in swirls and linear patterns develop along the lines of Blaschko. The ichthyosis tends to improve with age and might be so subtle in adulthood that it can be easily missed.
Hearing loss, congenital cardiac defects, cleft palate, brain anomalies and renal anomalies have been reported . The prognosis is generally good if the child survives infancy. Intellect is typically normal and combined with growth retardation gives a false impression that the child is smarter for the age as lay people easily underestimate the age of the affected patient.
Nearly two-thirds of patients have cataracts at birth  (see Fig. 21.4). They are often asymmetric or even unilateral reflecting the variable X inactivation. Other eye abnormalities that have been reported include microphthalmia, nystagmus, glaucoma and optic nerve atrophy [167, 168]. Vitreoretinal abnormalities in the form of unusual vitreoretinal tractional complexes with underlying retinal pigment epithelium disturbance have been reported .
Chondrodysplasia punctata . Partial cataract in a child with X linked Chondrodysplasia punctate (Photo courtesy Dr. P. Vijayalakshmi, Aravind Eye Care System, Madurai)
There are no specific diagnostic criteria. It is a clinical diagnosis based on the constellation of clinical findings involving skeletal, ophthalmological and dermatological findings. The radiographic appearance of punctate stippling is highly suggestive of the diagnosis. Plasma sterol analysis of scales from skin lesions, or cultured lymphoblasts or fibroblasts showing increased concentration of 8-cholestenol and 8-dehydrocholesterol strongly support the diagnosis. DNA testing is available.
Standard interventions are required for systemic abnormalities like hearing loss, cardiac and renal abnormalities. Orthopedic and dermatological consults should be arranged.
Standard interventions are required for Ophthalmologic abnormalities.
Cockayne syndrome is an autosomal recessive syndrome of premature aging characterized by growth failure, developmental delay, characteristic facies, behavioral and intellectual decline with early mortality and ocular manifestations. There are three subtypes . Type 1 is the classic form and more common than the other subtypes. Type II is the most severe form and manifests prenatally. Type III is a milder form with late onset. The phenotypic spectrum of Cockayne syndrome also includes a fourth condition with overlapping features of Xeroderma pigmentosa and Cockayne syndrome (see Fig. 21.5c). Type I alone has diagnostic criteria. The presence of two major and three minor criteria in an older child is required for making the diagnosis. The presence of two major criteria alone in an infant is sufficient for a diagnosis.
Cockayne syndrome . (a) This patient with Cockayne syndrome has deep set eyes (enophthalmos), lagophthalmos and small pupils. She also has cataract. She had retinal dystrophy. (b) Contractures are shown in the hand of her sibling, who also was affected with Cockayne syndrome. (c) This child has Xeroderma pigmentosa and Cockayne syndrome (Photo courtesy Dr. P. Vijayalakshmi, Aravind Eye Care System, Madurai)
Two major genes are currently known, bilallelic mutations of which cause Cockayne syndrome: excision repair cross-complementation group 6 and Group 8 (ERCC6 and ERCC8). Mutations in other genes ERCC1 cause Cockayne syndrome type 2 and COFS . Mutations in ERCC4 cause Type 1. These genes are responsible for making proteins CSB and CSA respectively which actively play a role in repairing defective DNA. ERCC8 is located at 5q12.1 and ERCC6 at 10q11.23. There is no specific genotype-phenotype correlation. Mutations in ERCC6 account for 65 % and ERCC8 account for 35 % of the cases with Cockayne syndrome [171, 172]. A mild UV-sensitive syndrome has been reported due to a null mutation of ERCC6 .
DNA is susceptible to damage by ultraviolet rays from the sun and by toxic chemicals, radiation, and free radicals. However normal DNA has the ability to rectify these errors by several repair mechanisms. Mutations in these two genes result in proteins that are unable to participate in some of the repair mechanisms of defective DNA resulting in progressive cumulative errors finally resulting in premature cell death . There appears to be a preferential loss of function to repair active genes .
Edward Alfred Cockayne first described most of the features of Cockayne syndrome in 1933 .
The incidence of Cockayne syndrome is approximately 2.7 per million births in Western Europe. This disease is probably under diagnosed and under reported .
The systemic features include neurological, dermatological, skeletal, dental and hearing abnormalities. Postnatal severe growth failure and neurological deterioration are the hallmark features. Signs of growth failure occur within the first 2 years of birth in the classic form and are evident at birth in type 2. The neurological findings include hypertonia, hypo or hyper-reflexia, tremor, ataxia and hearing loss. Neuroimaging often shows hypomyelination, supratentorial white matter loss, cerebellar atrophy or hypoplasia. Bilateral putaminal calcifications often occur in classic and late onset Cockayne syndrome. In addition to these findings cortical calcifications occur more often in earlyonset Cockayne syndrome . A typical stooped posture develops giving the appearance of horse riding stance due to contractures involving the knee joints. Contractures also develop in fingers and toes (see Fig. 21.5b). Dermatological findings include thinning of hair and skin. Cutaneous photosensitivity occurs and is especially more prominent in the variant that has overlapping features of Xeroderma pigmentosa. Dental abnormalities and caries are seen in later childhood. Other manifestations include endocrine abnormalities, renal abnormalities and hepato-splenomegaly . Unlike other disorders that occur due to defective DNA repair, cancers are not common in Cockayne syndrome . The mean age of death is 12 years but survival into the second or third decade has been reported . In the variant with overlapping features with Xeroderma pigmentosa (see Fig. 21.5c), ocular surface neoplasms occur. The prognosis for life is poor with mortality within the first two decades.
Newborns with Type 2 present with severe prenatal growth retardation and then show minimal or no postnatal neurological development. Extensive contractures of the spine and other joints commonly occur. These findings contribute to mortality within the first decade.
Enophthalmos, microphthalmia, congenital cataract, and miosis often occur  (see Fig. 21.5a). Pigmentary retinopathy associated with abnormal electroretinogram is the most consistent and common finding although the retinal exam is limited by miosis . Refractive errors, mainly hyperopia, strabismus and nystagmus also occur . Optic atrophy may occur in isolation or subsequent to pigmentary retinopathy . Corneal opacity and reduced lacrimation have been reported . Corneal perforation has also been reported .
Diagnosis is based on the diagnostic criteria in Type 1. The diagnosis becomes more evident with progression of the condition. The main differential diagnoses include cerebro-oculo-facial syndrome (COFS ) is considered as an allelic form of CS, and has overlapping features especially with CS type II and the most severe cases of the CS phenotypic spectrum . Type II shares features with Cerebro-oculo-facial syndrome COFS . DNA testing is available. Other conditions that cause microcephaly and cataract can be differentiated by the sunken eye appearance and retinal dystrophy seen in Cockayne. Congenital infections can simulate Cockayne syndrome due to intracranial calcification. Other disorders due to defective DNA repair such as Blooms syndrome and Xeroderma Pigmentosa and syndromes with premature aging share some clinical features with Cockayne syndrome
. Molecular genetic testing is available to confirm the diagnosis (Table 21.3).
Cockayne syndrome: Diagnostic Criteria and Clinical Features
Postnatal growth failure
Progressive microcephaly and neurologic dysfunction
Cutaneous photosensitivity with or without thin or dry skin or hair
Demyelinating peripheral neuropathy diagnosed by electromyography, nerve conduction testing, and/or nerve biopsy
Pigmentary retinopathy and/or cataracts
Sensorineural hearing loss
Dental anomalies, including dental caries, enamel hypoplasia, anomalies of tooth number, tooth size and shape
Cachectic dwarfism with thinning of the skin and hair, sunken eyes, and a stooped standing posture
Characteristic radiographic findings of thickening of the calvarium, sclerotic epiphyses, vertebral and pelvic abnormalities
Infants: 2 Major alone is sufficient for diagnosis
In Older children, 2 Major + 3 minor criteria is required for making a diagnosis
Perhaps the most difficult aspect of ophthalmic management is the limitations imposed by the miosis. This may artifactually reduce electroretinogram responsiveness and complicate cataract surgery. Appropriate surgical techniques are required for the latter. Viusal prognosis is poor due to the retinal dystrophy.
Monitoring of growth and developmental assessment is necessary. The prognosis for life is poor due to progressive nature of the condition and failure to thrive. Children are at higher risk for anesthesia due to difficulties in airway management and higher risk of gastric aspiration. Laryngeal mask airway appears to be safer than intubation [186, 187].
Cornelia De Lange Syndrome
Cornelia de Lange Syndrome (CdLS) is a developmental malformation syndrome characterized by short stature, intellectual disability, characteristic dysmorphic facial features, hirsutism, and limb abnormalities. Lifespan may be reduced particularly in more severely affected persons with major malformations but more mildly affected individuals have lived well into their 40s and 50s.
A diagnosis of CdLS is made based on any one of the criteria.
A disease causing mutation of the genes NIPBL, SMC1A or SMC3 by mutation analysis.
Criteria for facial features + 2 of (growth/development/behavior)
Criteria for facial features + 3 other criteria (growth/development/behavior + 2 from other category)
The diagnostic criteria is shown in Tables 21.4 and 21.5
Cornelia de Lange syndrome : diagnostic criteria and clincial features
CdLS: diagnostic criteria a
A disease causing mutation of the genes NIPBL, SMC1A or SMC3 by mutation analysis OR
Criteria for facial features + 2 of (growth/development/behavior) OR
Criteria for facial features + 3 other criteria (growth/development/behavior + 2 from other category)
Eyebrows that meet at the midline and > three or more of the following:
Short nose, anteverted nostrils
Long, prominent area between upper lip and nose
Broad or depressed nasal bridge
Small or square chin
Thin lips, downturned corners
Widely spaced or absent teeth
(> two or more of the following)
Weight below fifth percentile for age
Height/length below fifth percentile for age
Head circumference below fifth percentile for age
(> one or more of the following)
Developmental delays or intellectual disability, with speech more affected than motor skills
(> two or more of the following)
Attention deficit disorder plus hyperactivity
Extreme shyness or withdrawal
Cornelia de Lange syndrome : diagnostic criteria and clincial features
Musculoskeletal (> one or more of the following)
Absent arms or forearms
Three or more of the following or small hands and feet and/or missing digits with two or more of the following
Fifth finger Clinodactyly
Abnormal palmar crease
Dislocated elbow/abnormal elbow extension
Short first knuckle/proximally placed thumb
Partial webbing between second and third toes
Chest or sternum deformity
Hip dislocation or dysplasia
Neurosensory/skin (three or more of the following)
Tear duct malformation or inflammation of eyelid
Major eye malformation or peripapillary
Deafness or hearing loss
Mottled appearance to skin
Excessive body hair
Small nipples and/or belly button
Other major systems (three or more of the following)
Cleft palate or submucous cleft palate
Congenital heart disease
Abnormally placed opening of urethra on penis
Renal or urinary tract malformation
Muatations in one of six genes can cause CdLS. All five genes, NIPBL, SMC1A, SMC3, HDAC8, EP300 and RAD21, encode components of the cohesion complex. A milder phenotype with characteristic facial features but with less severe cognitive and limb involvement is seen in individuals with mutations in SMC1A and SMC3 NIPBL, EP300 and SMC3-related CdLS have an autosomal dominant pattern of inheritance. HADC8 and SMC1A-related CdLS are X-linked recessive. The EP300 phenotype tends to be milder. Patients with mutations in HDAC8 have some atypical features including large anterior fontanel, broader nasal root, hooded eyelids and a pleasant personality . Patients with mutations in RAD21 show growth retardation, minor skeletal anomalies and facial features that overlap with typical CdLS. The phenotype is milder .
The protein products of the genes appear to play an important role in regulating the structure and organization of chromosomes and are also involved in the repair of damaged DNA. They influence the activity of other genes in the developing limbs, face, and other parts of the body.
A German physician Brachmann first described an autopsy of an affected child, but it was Dutch pediatrician Cornelia de Lange who described two surviving children with features of this syndrome. The syndrome is sometimes referred to as Brachmann-de Lange syndrome.
The approximate incidence of this syndrome is 0.6–10 in 100,000.
The dysmorphic features include small or depressed nasal bridge with anteverted nares, small or square chin, long philtrum, thin vermilion border of upper lip, down turned corners of the mouth (“carp shaped”), high arched palate (or cleft palate), micrognathia and small, widely spaced teeth or oligodontia. Patient may show hirsutism as well. Other possible findings include small nipples, small umbilicus and cutis marmorata.
Weight, head circumference and height are all usually less than fifth percentile both prenatally and after birth. Proportionate short stature occurs. There appears to be a genotype-phenotype correlation between the degree of growth, developmental delay and limb defects .
Development and Behavior
A wide range of developmental delays and intellectual disability is seen. There is also a wide spectrum of behavioral patterns including attention deficit disorder, obsessive compulsive disorder, anxiety, aggression, self-injurious behavior and some patients show autistic features. Children are often non verbal even in the presence of normal hearing.
Sensorineural hearing loss is seen in 80 % of children with CdLS . Seizures. Some children have a low pitched cry which tends to disappear in late infancy.
Limb reduction defects are a cardinal feature often with oligodactyly, in particular a single digit. In mildly affected children, there is only small hands and feet. Patients with CdLS are also prone to Raynaud phenomena. Clinodactyly, abnormal palmar crease, radial head dislocation, difficulty in elbow extension, short first metacarpal, proximally placed thumb, bunion, partial syndactyly, scoliosis, pectus excavatum and hip dysplasia or dislocation and all been reported.
The most common cause of death and also behavioural abnormalties are related to the gastrointestinal tract, in particular gastroesophageal reflux. Other findings include gastrointestinal malformation, and uncommonly, diaphragmatic hernia. Pyloric stenosis is the most frequent cause of persistent vomiting in the newborn period.
Approximately 25 % of patients with CdLS have congenital heart disease . Ventricular septal defects, atrial septal defects, pulmonic stenosis, tetralogy of Fallot, hypoplastic left heart syndrome, and bicuspid aortic valve occur in decreasing order of frequency.
Micropenis, hypospadias, cryptorchidism, genitourinary malformations have been reported .
Synophrys and long eye lashes although not specific, are seen in over 95 % of children with CdLS. A down sloping V-shaped configuration of the eyebrows as they met and extended onto the upper part of the nasal bridge is common. Brow hypertrichosis may be observed. Down-slanting palpebral fissures are less common. Congenital ptosis with poor levator function may be unilateral or bilateral. Severe ptosis was reported to be found among individuals with truncating (nonsense and frame shift) mutations as compared with individuals with missense mutations . Blepahritis with recurrent blepharoconjunctivitis is extremely common and often misdiagnosed as nasolacrimal duct obstruction which is also if high incidence. Other findings include strabismus, nystagmus, and mild microcornea . In almost all children, fundus examination shows a peripapillary pigment ring. High myopia is frequent but retinal detachment may either be due to the myopia or self induced trauma. Less common ophthalmologic abnormalities include glaucoma, cataract astigmatism, optic atrophy, and coloboma of the optic nerve [195–197]. Other findings include ptosis, blepharitis, tear duct malformation, myopia more than 6 D, and peripapillary pigmentation.
A diagnosis is done based on clinical features and the diagnostic criteria showed in Table 21.6. DNA testing is available as a panel. Fetal alcohol syndrome shares several features with CdLS. Those include intrauterine growth retardation, failure to thrive, developmental abnormalities, microcephaly, facial hirsutism short palpebral apertures, short upturned nose, smooth underdeveloped philtrum, thin upper lip, and cardiac abnormalities. A history of alcohol use during pregnancy provides further clues to the correct diagnosis. Robert syndrome is also a differential diagnosis.
Usher syndrome : types, genes, proteins and major clincial feature
Other main findings
Does not exist
Congenital profound bilateral
No vestibular response
Early onset of RP
Delayed onset of walking
Mild to severe congenital
Normal vestibular function
No delay in onset of walking
Post lingual progressive
Variable vestibular function
Late onset RP
Approximately half of these children have a behavioral profile that is characterized by an extreme aversion to touching of their face. This makes glasses, often need for myopia, quite difficult. Contact lens has been successfully used by a few families. The developmental delay may preclude the need for a distant focal point and myopia may even be advantageous. Consideration should be given to examination under anesthesia for identification of treatable peripheral retinal breaks in highly myopic children to prevent retinal detachment. Care during anesthesia is required as some of these patients are predisposed to malignant hyperthermia .
Lid hygiene with baby shampoos scrubs has proven to be extremely effective in this patient population in reduction of recurrent blepharoconjunctivitis and also avoiding nasolacrimal duct surgery. It is recommended that trial of this therapy be used in all patients with CdLS prior to nasolacrimal surgery unless there is clearly an anatomic malformation.
Some children have such severe congenital ptosis that there chin lift precludes ambulation. Early surgery, particularly when ambulation may be developmentally expected, can be very beneficial. Levator slings are usually the first procedure.
De Morsier Syndrome (MIM 182230)
The cardinal feature of De Morsier syndrome is septo-optic dysplasia (SOD), an early forebrain developmental anomaly with ocular and neurological abnormalities. Some reserve the eponym for those children with a characteristic cranoiofacial dysmorphism including broad forehead, typical facies and enlarged anterior fontanelle. SOD is usually characterized by optic nerve hypoplasia, pituitary hormone abnormalities secondary to pituitary hypoplasia and midline brain anomalies including agenesis of the corpus callosum and septum pellucidum. All the three features are present only in 30 % of the patients. The diagnosis of SOD is a clinical diagnosis and can be made if the patient has at least two of the three clinical features. The presence of only one clinical feature is being currently debated to represent a possible milder form of the spectrum of this condition . Other brain findings may include siezures, cortical heteropias and other neuronal migration abnormalities such as schizencephaly.
Current research suggests a combination of genetic and environmental factors in the pathogenesis of SOD. The environmental risk factors that have been proposed include viral infections and specific medications. The disorder is usually autosomal dominant however and may be associated with mutations in HESX1 . This gene plays a critical role in embryonic development of the eyes, the pituitary gland, and the forebrain. HESX1 is a paired-like homeobox gene, which acts as a transcriptional repressor and it is one of the earliest markers of murine pituitary development. The frequency of pathological genetic mutations reported so far is very low and mutations have not been identified in many familial cases possibly suggesting the role of new genes. Disruption in blood flow to certain areas of the brain during critical periods of development due to genetic and environmental factors has also been implicated [200, 201].
Septo-optic dysplasia has a reported incidence of 1 in 10,000 newborns . It is more common in children born to young mothers. The incidence of true de Morsier syndrome is much lower as SOD can be part of many other syndromes.
The most common endocrine abnormality is growth hormone deficiency. Thyroid hormone deficiency may occur. Sudden death has been reported due to disruption of the corticosteroid axis . Panhypopituitarism with hypoglycemia, diabetes insipidus, reduced response to thyroid stimulating hormone, and hypogonadotropic hypogonadism can occur. SOD can be associated with precocious puberty secondary to hypothalamic dysfunction, or secondary to LH and FSH deficiency.
Seizures, developmental delay, and cerebral palsy are the most frequent neurologic associations seen with SOD . The classic MRI finding is absence of the pituitary infundibulum and an ectopic posterior pituitary bright spot, often within the stalk. Other associated brain abnormalities include s cavum septum pellucidum, cerebellar hypoplasia, and aplasia of the fornix and Dandy-Walker malformation. Midline brain defects, including agenesis of the septum pellucidum and/or corpus callosum, are present .
Other associated findings include obesity, autistic behavior, developmental delays, hearing impairment and temperature instability. Limb malformations have been associated with some patients with SOD and support possible vascular disruption etiology . Adrenal crisis can be precipitated by fever and dehydration due to corticotrophin deficiency resulting in sudden death . Hypothermia and temperature instability also can result in sudden death.
The characteristic finding is the presence of optic nerve hypoplasia. The hypoplasia is usually bilateral, but can be unilateral or asymmetric. In severe cases, ON aplasia may occur with a globe, but no identifiable optic nerve(s) or chiasm. Unilateral hypoplasia often causes strabismus and bilateral optic nerve hypoplasia may cause nystagmus. The classic hallmark of optic nerve hypoplasia is the presence of the double ring sign. The outer ring corresponds to the junction of the sclera with the lamina cribrosa and the inner ring corresponds to the actual optic nerve . Other ophthalmological findings may include primitive, disorganized or tortuous retinal vascular patterns, foveal hypoplasiaor optioc atrophy. Astigmatism and amblyopia may further compound the visual loss . Occlusion therapy and refractive correction can optimize visual outcomes Visual acuity is difficult to predict based solely on the appearance of the optic nerve. Microphthalmia and other developmental ocular abnormalities may also be seen in combination with features of SOD .
There are currently no diagnostic criteria. Newborns with hypoplastic optic nerves, hypoglycemia, jaundice, undescended testes, large anterior fontanelles in the absence of increased intracranial pressure, with or without other associated midline abnormalities should raise strong suspicion of the diagnosis of SOD. Clinical ophthalmic examination and neuroimaging greatly assists in arriving at the correct diagnosis. B scan ultrasonography and MRI can be used to demonstrate the small optic nerves although with the latter one must be cautious that the interpretation is not a result of the MRI cut. Careful clinical examination is needed, particularly in mild cases. Identification of anomalous retinal vessel patterns emanating from the optic nerve and an increased distance between the nerve and the fovea may be subtle clues to the presence of optic nerve hypoplasia. When ordering neuroimaging to confirm the diagnosis of SOD, it is important to specifically request adequate cuts of the pituitary gland and its infundibular stalk. Hormonal testing should include thyroid function even if the neonatal screen was reported as normal. Additional hormonal testing can be conducted as indicated. Patterns of restricted growth are worrisome for growth hormone reduction.
Although HESX1 is available for clinical testing, there are likely other genes involved in the causation of SOD. Multiple syndromes may have optic nerve hypoplasia or SOD as a manifestation. These can be recognized on the basis of other ocular and/or systemic findings. Clinical genetic testing is available for the HESX1 gene. OTX2 and SOX2 mutations can cause a picture that resembles SOD with an ophthalmia or microphthalmia.
Hormonal replacement therapy may be indicated. Ongoing monitoring of growth is essential. The prognosis is better with early diagnosis as hormonal abnormalities can be corrected earlier and risk for hypoglycemia, adrenal crisis can be reduced or avoided.
Comprehensive ophthalmic assessment including careful cycloplegic refraction is required. Patching treatment for amblyopia is indicated in unilateral optic nerve hypoplasia.
Joubert Syndrome (Classic) and Its Related Disorders (JSRD )
Classic Joubert syndrome (JS) is characterized by congenital malformation of the brainstem, in particular cerebellar vermis hypoplasia or aplasia causing a characteristic finding in MRI called the “molar tooth sign ” . Patients usually have hypotonia and developmental delay. Dysregulation of breathing results in episodic tachypnea or apnea. Ataxia and ocular abnormalities in the form of atypical movement disorders and retinal dystrophy can occur.
Joubert syndrome and related disorders (JSRD ) includes conditions that share the molar tooth sign and the clinical features of classic Joubert syndrome but have other organ system involvement.
The syndrome is genetically very heterogeneous. Currently, 23 genes and several loci have been associated with Joubert syndrome and JSRD . These account only for approximately 50 % of affected patients. Autosomal recessive inheritance is the most common pattern of inheritance. An X linked recessive form due to mutations in OFD1 also occurs . A digenic pattern of inheritance also has been reported as well .
The syndrome was first described by Marie Joubert in 1969, in siblings from a large French-Canadian family with intellectual disability, ataxia, abnormal eye movement and agenesis of the cerebellar vermis presenting with episodic tachypnea . The designation for the syndrome was suggested by Boltshauser and Islerin 1977 . The disease defining molar tooth sign was described later .
The prevalence of Joubert syndrome is approximately 1 in 100,000. Many studies suggest that this could be an underestimate .
A spectrum of systemic findings occurs depending upon the involved gene and hence a very thorough systemic examination will greatly assist the clinician in planning appropriate genetic testing (Table 21.6). Some of the systemic manifestations do not have any genotype-phenotype correlations.
The molar tooth sign is the most consistent finding and its presence is critical for making the diagnosis. It is characterized by the appearance of the brain stem in the shape of a molar tooth at the level of junction of midbrain and pons (see Fig. 21.6). The sign comprises an elongated, thick, and mal-oriented superior cerebellar peduncles, deep interpeduncular fossa and cerebellar vermis hypoplasia . This sign has also been demonstrated sometimes by fetal MRI making prenatal diagnosis in some of the patients . Hypotonia, ataxia, developmental delays and intellectual disability occur:intellectual disability can vary from mild to severe but is usually moderate . The presence of ventriculomegaly and/or seizures in a patient with JSRD should prompt testing for CC2D2A-related JS .
Molar tooth sign in JSRD . Molar tooth sign in Joubert syndrome caused by elongated, thick, and mal-oriented superiorcerebellar peduncles (blue arrows), deep interpeduncular fossa (red arrow) and cerebellar vermis hypoplasia (yellow arrow) (Photo courtesy Dr. P. Vijayalakshmi, Aravind Eye Care System, Madurai)
Episodic apnea and tachypnea can occur in infancy and usually improves with age . Hence birth history regarding apneic and tachypneic spells provides important diagnostic clues in an infant with retinal dystrophy and abnormal ocular movements. The combination of hypotonia, tongue hypertrophy and or obesity often predisposes to obstructive sleep apnea .
Juvenile nephronophthisis is characterized a chronic tubule-interstitial nephropathy that may progress to end stage renal disease. Cysts can occur at later stages. An adult polycystic kidney disease like phenotype has been linked to mutations in the gene TMEM67 .
Retinal involvement usually has coexistent renal cystic involvement and was referred earlier as Dekaban-Arima syndrome .
Some of the patients with JSRD have congenital hepatic fibrosis. These patients also have chorioretinal coloboma and sometimes coexistent renal disease. COACH syndrome is an acronym for coloboma, cognitive impairment (“oligophrenia”), ataxia, cerebellar vermis hypoplasia, and hepatic fibrosis .
The nystagmus is usually bilateral, conjugate and horizontal. Vertical and torsional nystagmus may occur. A see saw form of nystagmus has also been reported . Pendular nystagmus and gaze-holding nystagmus have been reported . Vestibulo-ocular reflex is present but patients may have poor ability to cancel the vestibulo-ocular reflex horizontally and vertically . Tonic deviation of their eyes laterally and alternating hyperdeviation have also been reported .
It is horizontal in nature and might be associated with compensatory head thrusting .
Abnormalities occur not only in saccades but also in pursuits .
Bilateral and asymmetric ptosis may occur .
The coexistence of fundus coloboma and retinal dystrophy in an infant with oculomotor abnormality should raise the suspicion of JSRD . Iris coloboma may or may not be present.
A dystrophic retinal appearance or a frank retinal dystrophy might be seen . Electro retinogram is usually attenuated or might be absent. Visual evoked potential may show asymmetric responses suggesting abnormalities in optic nerve decussation. Optic nerve dysplasia has been reported . Disc coloboma and  Optic disc drusen have also been reported . Iris neovascularization has been reported .
The most consistent and obligatory sign that is required for diagnosis is the presence of the molar tooth sign .
A diagnosis of Classic or pure Joubert syndrome is based on the presence of three primary diagnostic criteria.
Molar tooth sign
Hypotonia during infancy with later development of ataxia
Developmental delays or intellectual disability
The molar tooth sign is also noted in disorders that were initially identified as distinct syndromes. These include Senior-Loken syndrome, COACH syndrome , Varadi-Papp syndrome and Dekaban-Arima syndrome . These syndromes now form a spectrum under JSRD .
Molar tooth sign may also be found in genetically related disorders like nephronophthisis, Cogan syndrome , Meckel syndrome , MORM, Oral-facial-digital syndrome , Hydrolethalus syndrome , Acrocallosal syndrome (ACLS ).
Periodic monitoring of liver, hepatic function is indicated in the absence of genetic testing. Polysomnography may be required to detect sleep apnea.
Ptosis and strabismus are managed as indicated. Refractive errors need attention. There is no specific treatment for oculomotor apraxia.
Lowe Syndrome (OCRL MIM 309000)
Lowe syndrome (Oculo-cerebro-renal syndrome of Lowe, OCRL) is an X-linked recessive disorder which is characterized by involvement of the eyes, central nervous system and kidneys.
Lowe syndrome is caused by mutations in the OCRL1 gene at Xq25-q26 which codes for the enzyme inositol polyphosphate 5-phosphatase. There is currently no known genotype-phenotype correlation. Sequence analysis detects mutations in 95 % of males and 95 % of female carriers. Several mutations, including truncation mutations, missense mutations, and large deletions have been reported . OCRL plays a role in membrane trafficking.
The syndrome was first described in 1952 by Charles Lowe and his colleagues .
The incidence of Lowe syndrome is approximately 1 in 1,000,000 worldwide .
Dysmorphic Facial Features
Facial dysmorphisms are often present and consist in frontal bossing, deep-set eyes, chubby cheeks and a fair complexion .
Gross hypotonia is evident at birth. This also contributes to a significant delay in motor development and feeding difficulties. Deep tendon reflexes are often absent. Seizures are common. Intellectual disability and learning disability is seen to some degree in all affected males. Maladaptive behavior is also common including temper tantrums, irritability, stereotypy/mannerisms, obsessions/unusual preoccupations, and negativism .
Proximal tubular dysfunction is the main abnormality (Fanconi syndrome). Fanconi Syndrome is a proximal renal tubular defect which results in loss of potassium, phosphorus, bicarbonate, uric acid, glucose, and amino acid. Loss of bicarbonate results in acidosis. Renal phosphate wasting results in the development of renal rickets, osteomalacia and pathological fractures. Loss of bicarbonate, salt and water results in failure to thrive. Hypercalciuria , leads to nephrocalcinosis and nephrolithiasis can occur. All affected boys have some degree of proteinuria. Chronic renal failure accounts for significant morbidity and results in end stage renal failure. Vitamin D-resistant rickets, amino aciduria (relative sparing of branched amino acids), and reduced ammonia production by the kidney occur. Hypokalemia can occur. Nephrocalcinosis and nephrolithiasis may be a result of the Fanconi syndrome or due to vitamin D therapy for rickets.
Gastroesophageal reflux, crytporchidism, inguinal hernia and atelectasis, pneumonia, or chronic lung disease, joint dislocation due to hypermobility, delayed onset of puberty and dental malformations can occur. The most frequent causes of death include respiratory illness, and seizures. Patients often experience failure to thrive and short stature; undescended testis may be seen in up to first/third of patients .
Female Carriers of Lowe Syndrome
Congenital cataract occurs in all affected male children. They are often dense but begin as posterior polar opacities. Lowe syndrome is one of the few conditions which have coexistent congenital cataract and glaucoma . Other ocular manifestations include microphthalmia, band keratopathy, and corneal keloids or scars. The eyes often appear enophthalmic even in the absence of microphthalmia. Nystagmus and strabismus are secondary findings. Retinal dysfuction may also be observed . Most carrier females especially post pubertal females tend to have fine irregular, punctate, smooth, radially oriented white to gray opacities in the lens cortex sparing the nucleus. Some of the carriers have snow flake like opacities .
The triad of congenital cataract, hypotonia and renal tubular dysfunction in a male child may be considered as a diagnostic triad. Molecular genetic testing is available on a clinical basis. Enzyme assay in cultured fibroblasts is perhaps the best way to make the diagnosis. In affected males, enzyme levels are usually below 10 %. Carrier females often have cataract. Dilated slit-lamp biomicroscopy examination to detect cataract is a highly sensitive test for detection of carriers .
Differential diagnosis includes Cystinosis, Nance Horan syndrome , congenital myotonic dystrophy, Smith-Lemli-Opitz syndrome and peroxisomal disorders such as Zellweger syndrome. Nance-Horan syndrome is also an X linked recessive disorder with cataract and dental anoamlies. However they lack the facial appearance of sunken orbits and bitemporal hollowing and the renal abnormalities seen in Lowe syndrome. Peroxisomal disorders are characterized by hypotonia, poor feeding and have distinctive facies different form Lowe syndrome (See under perxosomal disorders ). Neonatal seizures are common. Bony stippling (chondrodysplasia punctata) of the patella (e) and other long bones may occur. Other findings that may be seen in older children include retinal dystrophy, sensorineural hearing loss, developmental delay, hypotonia, and liver dysfunction. Renal involvement also assists in differentiating Lowe syndrome from other conditions that cause congenital cataract and hypotonia like peroxisomal disorders, mitochondriopathies or congenital myopathies. Low molecular proteinuria is a consistent and a very sensitive marker for renal involvement. OCRL should be considered in boys with congenital cataracts and glomerular disease, even in the absence of any significant renal tubular abnormality . Dent disease shares several clinical features with Lowe syndrome. Dent disease, also an X linked recessive disorder is characterized by proximal tubule (PT) dysfunction with low-molecular-weight (LMW) proteinuria and hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure and is seen only in males. Females are carriers. Mutations in CLCN5 cause (Dent disease type 1) and mutations in OCRL1 cause (Dent disease type 2). However CLCN5 gene mutations accounts for most Dent disease. Cataracts and neurologic deficits which are always seen in Lowe syndrome do not occur in Dent disease.
Hypotonia causes issues with feeding and nutrition. Associated gastroesophageal reflux further complicates nutrition and development. Renal function monitoring and prevention of development of rickets is essential. As these patients are very susceptible to electrolyte and metabolic imbalance especially during illness, dehydration or stress as in surgery, replacement of fluids, electrolytes and bicarbonate is necessary prior surgery.
Cataract surgery is often complicated by the presence of coexisting glaucoma. Children may also need surgical procedures for glaucoma. The glaucoma is often difficult to manage. Visual rehabilitation is usually required and the prognosis is guarded.
Mitochondria are considered the powerhouse of the cell and are critical for generating ATP by oxidative phosphorylation. Mitochondria have their own genome separate from the nuclear DNA but their function also requires proteins that are encoded by nuclear DNA. Disorders of mitochondrial function can be due to mutations in mitochondrial or nuclear DNA . Only mutations in the mitochondrial genome have the mitochondrial pattern of matrilineal inheritance. Since the sperm does not contribute its mitochondria to the zygote, males do not transmit mitochondrial disease. Affected females can transmit the disease to all of their children, affecting both male and female children (with the exception of Leber hereditary optic neuropathy which is more common in male offspring).
Tissues with higher metabolic rate dependent on oxidative phosphorylation are most often affected including brain, muscles and muscles and hearing . The severity of the phenotype depends upon heteroplasmy [247, 248]. Homoplasmy is the state of having only healthy or only mutated mitochondria while heteroplasmy is the mixed population of normal and mutated mitochondria. The proportion of normal and abnormal mutant mitochondrial DNA in each tissue determines the severity and the threshold (proportion of abnormal mitochondria in each tissue required to manifest disease) for the disease manifestation . Patients should avoid medications that are toxic to mitochondria including aminoglycosides, valproate, fluoxetine, amitriptyline, chlorpromazine, haloperidol, diazepam, and alprazolam.
Other features often seen in most mitochondrial disorders like short stature, hearing loss, dementia, limb weakness, and diabetes mellitus may be seen.
Mitochondrial Encephalopathy, Lactic Acidosis and Stroke Like Episodes (MELAS MIM 540000)
This genetically heterogeneous disorder has multisystem involvement primarily involving the central nervous system and muscles.
MELAS is caused by mutations in mtDNA and is transmitted by maternal inheritance.
MELAS can result from mutations in any one of several genes, including MT-ND1, MT-ND5, MT-TH, MT-TL1, and MT-TV. MT-TL1 is responsible for most cases . Most of theses genes provide instructions for making transfer RNAs (tRNAs) Genetic counselling is complicated due to heteroplasmy for which the recurrence risk in not consistent even if the mutation is known. Males can be assured that their children will be unaffected. Genetic testing is available on a clinical basis. New in vitro fertilization techniques have been developed using a donor egg that has its nucleus removed and replaced by an unaffected donor mother’s nucleus. Though it is clear that mitochondrial mutations are responsible for MELAS, the exact mechanism as how these abnormal proteins result in a spectrum of clinical findings is still unclear.
It was first described in 1984 .
Mitochondrial diseases occur in about 1 in 4000 people. The exact incidence of MELAS is not known.
It typically begins during childhood. The symptoms usually begin with generalized tonic-clonic seizures, recurrent headaches, nausea, anorexia, and recurrent vomiting. Stroke like episodes occur following seizures. The episodes may be precipitated by physical exercise and heat. Febrile illness may trigger exacerbations. The severity of clinical manifestations depends upon heteroplasmy, a unique feature of all mitochondrial disorders.
The neurologic findings are usually the first symptoms to appear. These invariably occur in early childhood and almost all patients develop symptoms and signs before the beginning of the fourth decade. Stroke-like episodes are often precipitated by exercise. These “Stroke like episodes” are result of focal cerebral metabolic crisis and bear little resemblance to strokes of an atherosclerotic or thrombo-embolic etiology. This distinction is important to avoid misdiagnosis. Even in the absence of a focal deficit there may be focal EEG and MRI abnormalities. A stroke results in a permanent neurological deficit that persists more than 24 h. In a stroke like episode, the neurological function might fully recover after the episode but the resultant neuronal loss causes a gradual step-wise reduction in cerebral function . Transient hemiparesis and cortical blindness can occur after these episodes. Patients may also develop altered consciousness following these attacks. Many patients develop acute migraine during the stroke. Behavioral abnormalities and autistic behavior may occur . Hearing impairment may occur as a primary manifestation . Myoclonus , learning disability, cerebellar signs, increased CSF protein and basal ganglia calcification are some of the other neurological findings seen [255–257].
Some of the neuroimaging findings are transient, occurring only during the time of stroke-like episodes. MRI often shows increased T2 signal, typically involving the posterior cerebrum and do not conform to the distribution of major arteries. Diffusion-weighted MRI might show increased apparent diffusion coefficient (ADC) in stroke-like lesions. Vasogenic edema and in some patients cytotoxic edema is responsible for the imaging findings. A decrease in N-acetylaspartate and an increase in lactate have been reported in H-magnetic resonance spectroscopy .
Optic atrophy, pigmentary retinopathy and ophthalmoplegia are the common ophthalmic manifestations reported. Abnormal photopic and scotopic ERG can occur. Macular retinal pigment epithelial atrophy may be seen. A reversible, homonymous hemianopia, atypical retinitis pigmentosa with marked attenuation of the scotopic ERG, myopia and nuclear cataract has been reported in MELAS . A clinical presentation of Chronic Progressive external ophthalmoplegia (PEO) with diabetes mellitus (DM), cardiomyopathy and deafness has been reported .
The clinical triad of stroke like episodes, encephalopathy with seizures and dementia, and myopathy with lactic acidosis and red ragged fibers when present along with any two of the three following clinical features, recurrent headache, recurrent vomiting and normal early psychomotor development confirms the diagnosis of MELAS syndrome. Ragged red fibers on muscle biopsy are often diagnostic. In patients with CPEO, the mutation might be seen only in the muscle tissue and may be missed in other tissues.
Kearns-Sayre Syndrome (MIM 530000)
Kearns-Sayre is a multisystem disorder predominantly affecting the eyes, central nervous system, skeletal muscle, and heart. It is a form of chronic progressive external ophthalmoplegia. KSS is caused by large deletions of mitochondrial DNA (mtDNA), resulting in the loss of genes involved in the oxidative phosphorylation pathway.
This triad of CPEO, bilateral pigmentary retinopathy, and cardiac conduction abnormalities was first described in 1958 by Thomas P. Kearns (1922), MD and George Pomeroy Sayre (1911).
It occurs approximately in 1–3 per 100,000 individuals .
Several cardiac anomalies have been reported. The most serious concern for a patient with KSS is sudden cardiac death due to arrhythmias. Cardiac conduction disturbances are the most common. Atrioventricular block is the most common. Cardiac arrest has also been reported . Also co-inheritance of Long QT syndrome and KSS has been documented . Apart from the conduction disturbances, cardiomyopathy can occur .
Many endocrine abnormalities occur including hypoparathyroidism, menstrual abnormalities, growth hormone deficiency and diabetes mellitus occur . Short stature, gonadal failure, hyperaldosteronism, hypomagnesaemia, abnormalities in calcification of bone and tooth has also been reported  Mitochondria are a prerequisite for steroidogenesis as well as the secretion and action of insulin .
Seizures and strokes are rare in Kearne-Sayre syndrome. Cerebellar ataxia, intellectual deficit, dysarthria, bilateral facial weakness are some of the common neurological findings. Calcification of the basal ganglia has been reported. Cerebellar ataxia, increased CSF protein content cerebrospinal fluid (CSF) protein content above 100 mg/dL are important and one of them is required for making the diagnosis apart from the presence of the characteristic triad. Syncope is a manifestation of cardiac arrhythmia.
Sensory neural hearing loss can occur
This is usually bilateral. Rarely patients might develop external ophthalmoplegia ahead of ptosis and may cause diagnostic confusion. Since these patients have poor bells phenomenon, Crutch glasses are recommended.
It is the most common ocular manifestation of all mitochondrial myopathies. Though there is external ophthalmoplegia, patients usually do not complain of double vision, (even when ptosis does not obscure the visual axis). There is progressive limitation of all movements.
The most common form of retinal pigmentary retinopathy is salt and pepper retinopathy, which typically becomes more prominent with age . it is one of the diagnostic triads of KSS.
Cataract is Less Common
Corneal abnormalities are less common but have been reported and can precede systemic findings by several years .
This could follow optic neuritis .
It is characterized by the triad of pigmentary retinopathy (salt and pepper retinopathy), progressive external ophthalmoplegia and onset before 20 years old of age. The presence of these three features and at least one of the following is required to make the diagnosis: The other three features include cardiac conduction defects, increased CSF protein and cerebellar ataxia. Other features often seen in most mitochondrial disorders like short stature, hearing loss, dementia, limb weakness, and diabetes mellitus may be seen.