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 [33]. 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 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 syndrome was first described by Aicardi et al. [36], as a neurodevelopmental disorder that affects primarily females [37–39].

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 [40].

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.

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 [46]. Within lacunae, the RPE is typically absent, and the choroid and sclera are thin [47]. The reported eye findings can be unilateral or bilateral and can be grossly asymmetric. Other optic nerve abnormalities include optic nerve aplasia and hypoplasia [47]. 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.

Alagille syndrome (AGS; OMIM 118450) is a complex multisystem disorder involving predominantly the liver, heart, eyes, face, and skeleton [49]. 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. [50]. 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 [51], a revised diagnostic criterion has been recently proposed by Kamath et al. [52]. 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 % [53]. 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 .

The clinical condition was first reported by Alagille et al. in 1969 [50]. It was subsequently reported by Watson and Miller in 1973 [54], and again by Alagille et al. in 1975. Hence it is sometimes also referred to as Alagille–Watson syndrome.

The incidence of Alagille syndrome ALGS is estimated to be approximately 1 in 30,000–50,000 live births [55, 56].

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].

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 [78]. Retinal vascular and pigmentary changes, with macular pigment clumping, speckling and chorioretinal folds can occur [70].

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 [79].

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 [82]. 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 [83]. The recent revised criteria are shown in Table 21.1 [84]. 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.

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 [83]. Patients usually have worsening of all symptoms and signs by second/third decade resulting in reduced life expectancy due to progressive multisystem involvement.

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 [93]. The severity and age of onset of the retinal degeneration vary among affected individuals [94].

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

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 [95]. 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 [96]. 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 [99]. 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 [102].

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 [107]. 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.

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 [110]. 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 [113]. 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 [114].

The estimated incidence is approximately 1:160,000 in northern European populations and 1:13,500 in some Arab populations [115].

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 [124]. 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 [112].

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 [125].

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 [128]. 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 [129]. Penetrance appears to be 100 % in BPES1 and 96.5 % in BPES2 [130]. 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) [131]. 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 [129].

Occasionally individuals with BPES may have cytogenetic rearrangements, including interstitial deletions or translocations involving locus interface between 3q22.3 and 3q23 [132] Waardenburg [133] 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 [134].

Von Ammon’ first used the term blepharophimosis in 1841 [135]. However it was Vignes in 1889 that first associated blepharophimosis with ptosis and epicanthus inversus [136].

The exact frequency of BPES is unknown [137].

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.

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.

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 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 [143].

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.

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 [147]. Most patients have denovo mutations . Increased paternal age appears to be risk factor [148]. 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 .

Hall (1979) and Hittner et al. (1979) provided the first descriptions of this syndrome and hence the eponym Hall-Hittner syndrome was suggested, though the simplicity of the acronym CHARGE has withstood the test of time [149, 150].

CHARGE syndrome occurs in approximately 1 in 8500 to 10,000 individuals [151].

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.

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 [158]. Autosomal dominant and recessive forms also occur [2]. 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[9]-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 [159], 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) [160]. 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 [163].

Malou et al. suggested that the incidence could be 1 in 5, 00,000 [164].

Nearly two-thirds of patients have cataracts at birth [166] (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 [169].

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[9]-cholestenol and 8-dehydrocholesterol strongly support the diagnosis. DNA testing is available.

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 [170]. 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.

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 [173].

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 [174]. There appears to be a preferential loss of function to repair active genes [175].

Edward Alfred Cockayne first described most of the features of Cockayne syndrome in 1933 [176].

The incidence of Cockayne syndrome is approximately 2.7 per million births in Western Europe. This disease is probably under diagnosed and under reported [177].

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 [178]. 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 [179]. Unlike other disorders that occur due to defective DNA repair, cancers are not common in Cockayne syndrome [180]. The mean age of death is 12 years but survival into the second or third decade has been reported [181]. 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 [182] (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 [182]. Refractive errors, mainly hyperopia, strabismus and nystagmus also occur [182]. Optic atrophy may occur in isolation or subsequent to pigmentary retinopathy [183]. Corneal opacity and reduced lacrimation have been reported [184]. Corneal perforation has also been reported [183].

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 [185]. 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).

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.

The diagnostic criteria is shown in Tables 21.4 and 21.5

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 [188]. Patients with mutations in RAD21 show growth retardation, minor skeletal anomalies and facial features that overlap with typical CdLS. The phenotype is milder [189].

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.

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 [193]. 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 [194]. 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.

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 [199]. 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].

Reeves in 1941 first described this condition as absence of the septum pellucidum in association with optic nerve abnormalities. Association of pituitary abnormality was described subsequently [202]. It is equally common in both sexes and is more common in infants born to younger mothers [203].

Septo-optic dysplasia has a reported incidence of 1 in 10,000 newborns [204]. 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 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 [208]. 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 [209]. 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.

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 ” [210]. 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 [211]. A digenic pattern of inheritance also has been reported as well [212].

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 [213]. The designation for the syndrome was suggested by Boltshauser and Islerin 1977 [214]. The disease defining molar tooth sign was described later [215].

The prevalence of Joubert syndrome is approximately 1 in 100,000. Many studies suggest that this could be an underestimate [216].

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 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.

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 [233]. These syndromes now form a spectrum under JSRD [212].

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 ).

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 [234].

The incidence of Lowe syndrome is approximately 1 in 1,000,000 worldwide [235].

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 [238].

The clinical findings are highly variable due to the pattern of X inactivation (Lyonization) [239, 240].

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 [235]. 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 [241]. 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 [242].

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 [243].

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 [244]. 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.

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 [245]. 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 [246]. 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 [249]. 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.

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 [250]. 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 [251].

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.

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 [258]. A clinical presentation of Chronic Progressive external ophthalmoplegia (PEO) with diabetes mellitus (DM), cardiomyopathy and deafness has been reported [259].

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 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).

The syndrome was described by Kearns in 9 unrelated patients who had known positive family history [260]. Mitochondrial deletions as a cause of KSS were established in 1988 [261].

It occurs approximately in 1–3 per 100,000 individuals [262].

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.