Retinal dystrophies with systemic associations and the retinal ciliopathies

Introduction

Children affected by retinal degeneration associated with extraocular manifestations define the inherited systemic retinitis pigmentosa (RP) syndromes (retinal dystrophies related to inborn errors of metabolism are covered in Chapter 65 ) ( Tables 46.1 and 46.2 ). The gene or the group of genes involved in the syndrome belong to a specific biologic network whose mutations lead to retinal degeneration associated with manifestations in other organs defined by the specific biologic role of the protein. Retinal degeneration occurs in these syndromes by virtue of the biologic complexity of the retina. The photoreceptor cell is remarkably sensitive to alterations in many biologic pathways. The clinical presentation is often indistinguishable between syndromes with the classical features of retinal degeneration: night blindness, visual field constriction, and reduced visual acuity. In the early phases of the retinal degeneration, the fundus sometimes appears normal although the electroretinogram (ERG) is altered. Later, the fundus will acquire usual aspects observed in retinal degeneration: retinal pigmentary changes such as hypopigmentation and/or hyperpigmentation with clumping or formation of bone-spicules, retinal atrophy, optic disc pallor, narrowed vessels, and macular changes that are prominent and early in the cone–rod dystrophies.

Table 46.1

Main extraocular features found and the corresponding systemic retinitis pigmentosa (RP) syndrome

Extraocular clinical feature associated with RP in a child		Key feature found in systemic syndrome
Stature	Dwarfism Obesity	Cockayne syndrome (cachectic), spondylometaphyseal dysplasia or spondyloepiphyseal dysplasia associated with cone dystrophy Bardet–Biedl syndrome (BBS), Alström syndrome, Cohen syndrome (truncal), MORM (mental retardation, truncal obesity, retinal dystrophy, and micropenis) syndrome
Skeletal abnormality	Polydactyly Short ribs with abnormal thorax Various abnormal skeletal development	BBS, Joubert syndrome, Jeune syndrome Jeune syndrome Spondylometaphyseal dysplasia or spondyloepiphyseal dysplasia
Deafness		Usher syndrome (variable severity according to types), Alström syndrome (progressive starting in childhood)
CNS malformations	Cerebellar vermis agenesis (molar tooth)	Joubert syndrome
Kidney dysfunction	Polyuria-polydypsia Kidney failure	BBS, Alström syndrome, Jeune syndrome, Senior–Løken syndrome, Joubert syndrome
Endocrine dysfunction	Type 2 juvenile diabetes Pituitary deficiency	Alström syndrome Oliver–McFarlane syndrome
Cardiomyopathy		Alström syndrome
Cognitive impairment		Classical: Cohen syndrome, Joubert syndromeOccasional: BBS, Alström
Teeth	Amelogenesis imperfecta Prominent incisors	Jalili syndrome Cohen syndrome
Skin/hair	Ultraviolet sensitivity Alopecia – early hair loss	Cockayne syndrome Hypotrichosis with juvenile macular dystrophy; EEM (ectodermal dysplasia, ectrodactyly, macular dystrophy) syndrome Oliver–McFarlane syndrome; long eyelashes

Table 46.2

Main systemic retinitis pigmentosa syndromes

Name of the syndrome with retinal degeneration	Main diagnostic extraocular signs	Identified gene(s) (main genes – not exhaustive)	Pathogenesis
Usher syndrome type 1	Deafness: congenital and profound Vestibular dysfunction	MYO7A , CDH23 , USH1C , PCDH15 , SANS , CIB2	Stereocilia and photoreceptor development and function. Network of Usher proteins
Usher syndrome type 2	Deafness: congenital, moderate to severe No vestibular deficit	GPR98 , USH2A , WHRN , PDZD7 (modifier)	Stereocilia and photoreceptor development and function. Network of Usher proteins
Usher syndrome type 3	Late-onset rod–cone dystrophy Late-onset progressive deafness	USH3A ( CLRN1 ), HRAS1	Stereocilia and photoreceptor development and function. Network of Usher proteins
Bardet–Biedl syndrome	Polydactyly Obesity Intellectual disability Kidney dysfunction Urogenital malformation	BBS1 to BBS 24	Ciliopathy
Alström syndrome	Obesity Type 2 diabetes mellitus Deafness Cardiomyopathy Kidney dysfunction Liver dysfunction Growth and endocrine deficiency Occasional intellectual disability	ALSM1	Ciliopathy
MORM	Intellectual disability Truncal obesity Micropenis	INPP5E	Ciliopathy
Senior–Løken syndrome	Nephronophthisis	NPHP1 to 6 , SDCCAG8	Ciliopathy
Mainzer–Saldino syndrome	Renal dysplasia Cerebellar ataxia Skeletal dysplasia Cone-shaped epiphyses	IFT140	Ciliopathy
Joubert syndrome	Cerebellar vermis hypoplasia Ataxia Cognitive impairment Tachypnea Abnormal eye movements Kidney dysfunction Polydactyly	INPP5E , TMEM216 , NPHP1 , CEP290 , TMEM67 , RPGRIP1L , CC2D2A , CXORF5 , TTC21B , KIF7 , TCTN1 , TMEM237 , CEP41 , TMEM138 , C5ORF42 , TCTN3 , ZNF423 , TMEM231 , CSPP1 , PDE6D , KIAA0586 , TCTN2 , CEP104 , KIAA0556 , B9D1 , MKS1 , TMEM107 , ARMC9 , CEP120 , SUFU , PIBF1 , B9D2 , ARL3 , FAM149B1	Ciliopathy
Jeune syndrome(related to short rib thoracic dysplasia)	Severe constricted thorax Chondrodysplasia with short bones Kidney dysfunction Liver fibrosis	IFT80 , DYNC2H1 , TTC21B , WDR19 , NEK1 , WDR35 , WDR60 , IFT140 , IFT172 , WDR34 , CEP120 , KIAA0586 , DYNC2LI1 , IFT52 , TCTEX1D2 , IFT81 , INTU	Ciliopathy
Cohen syndrome	Myopia Facial gestalt Truncal obesity Prominent upper incisors Intermittent granulocytopenia Long tapered fingers Joint laxity Intellectual disability	VPS13B	Presumed vesicular transport
Cockayne syndrome (and overlapping with XP genes)	Cachectic dwarfism Deafness Optic atrophy Cataract UV sensitivity Neurodegeneration	CSA ( ERCC8 ), CSB ( ERCC6 ) and XPG/CS = ERCC5 ; XPB/CS = ERCC3 ; XPF/CS = ERCC4	Transcription factor-related Defective DNA repair
Jalili syndrome	Amelogenesis imperfecta	CNNM4	Metal transport protein
Hypotrichosis with juvenile macular dystrophy	Early hair loss	CDH3	Cadherin family
Ectodermal dysplasia, ectrodactyly, macular dystrophy (EEM) syndrome	Early hair loss Lobster-claw hands	CDH3	Cadherin family
Oliver–McFarlane syndrome	Long eyelashes Early hair loss Short stature – pituitary deficiency Developmental and neurologic impairment	PNPLA6
Boucher–Neuhauser syndrome	Spinocerebellar ataxia Hypogonadotropic hypogonadism	PNPLA6
Spondylometaphyseal dysplasia or spondyloepiphyseal dysplasia associated to cone dystrophy	Short stature Limb abnormalities	PCYT1A

All these syndromic conditions are rare inherited diseases; the most frequent syndromes are Usher syndrome (USH) and Bardet–Biedl syndrome (BBS).

Over the past two decades, most of the genes responsible for these genetically highly heterogenous conditions have been identified. This field will continue to greatly benefit from new genome exploration, especially high-throughput sequencing with next-generation sequencing (NGS) technologies, panel targeted sequencing, whole exome sequencing or whole genome sequencing). Molecular diagnosis and genetic counseling are constantly improving, especially for the syndromes which are highly heterogeneous. The classical syndromes illustrating this group of diseases are described, but a growing number of overlapping phenotypes have become evident as molecular investigations improve. Moreover, different pathogenic variants in the same gene may lead to different syndromes on the same clinical spectrum (see section “The ciliopathies”). Major clinical variability in each syndrome has been described. For some genes, specific mutations may lead to isolated features such as isolated RP (e.g. Usher syndrome gene USH2A or Bardet–Biedl genes BBS8 and BBS3 ). A child presenting with RP should be systematically evaluated for extraocular associated features (unless he/she is already known to be affected by a non-syndromic pathogenic variant). These conditions require multidisciplinary follow-up and management.

Holistic care is advocated taking into account the multiple associated disabilities. Many research approaches to alleviate the retinal degeneration are underway, including gene transfer and gene editing, pharmacological compounds, and cell therapies.

Usher syndrome: a deaf child who loses vision

In Usher syndrome, sensorineural deafness is associated with progressive retinal degeneration. USH occurs in 1 of every 10 deaf children (5% of all cases of congenital deafness). It is the most frequently inherited syndrome with deafness and is the most common syndrome among the deaf–blind. The syndrome is subdivided into three groups: Usher type 1 (USH1), type 2 (USH2), and type 3 (USH3). USH1 and 2 are usually diagnosed in early or late childhood, respectively, but may be diagnosed later in life as the visual impairment may be overlooked in a deaf child. Usher type 3 is much rarer; the onset of deafness is in late childhood and is followed by visual loss. It is more common in patients with a Finnish descent or those of Askenazi Jewish origin. Vestibular dysfunction is classically associated with USH1. Each type of Usher syndrome is autosomal recessive but genetically heterogeneous. For each type, a number of genes have been identified (see Table 46.1 ). Molecular studies have shown clinical overlap between the classical types USH1 and USH2. Some Usher genes can be involved in either isolated deafness ( MYO7A or CI2N for example) or isolated RP ( USH2A for example); therefore variants from genetic screening should be interpreted cautiously with respect to their prognostic implications. Cochlear implantation is highly recommended for these children (especially in USH1). No therapy is yet available for the retinal degeneration ( Fig. 46.1A–C ).

Fig. 46.1, Usher syndrome. (A) Fundus photograph of a 5-year-old patient with Usher syndrome type 1 due to MYO7A mutation. The patient first walked at age 24 months. The fundus shows very mild pigment epithelium irregularity and the electroretinogram is extinguished. (Bi) Audiogram of the same patient before implantation showing profound deafness. (Bii) Audiogram after cochlear implantation showing dramatic hearing improvement. (C) Photograph of the patient showing the cochlear implantation device. (Di) Fundus photograph of the right eye of a patient affected by Usher syndrome type 2 C (mutations in VLGR1G ). (Dii) Fundus photograph of the left eye of the same patient showing retinitis pigmentosa. (E) Schematic representation of an auditory sensory cell and of the tip link molecular complex.

Usher syndrome type 1: the most severe form

The child with USH1 is affected with congenital severe to profound sensorineural hearing loss associated with delayed sitting and walking due to abnormal vestibular function. Retinal degeneration occurs early in childhood. As early as 2 or 3 years old, the ERG can confirm the diagnosis of retinal degeneration although the fundus appears to be normal. Five causative genes are known and mutated in various proportions according to the studied population: myosin 7 A gene ( MYO7A or USH1A ) is recognized to be the main USH1 gene mutated in half of the cases, harmonin gene ( USH1C ), cadherin-related 23 gene ( CDH23 ; USH1D ), protocadherin-related 15 gene ( PCDH15 or USH1F ), sans gene ( USH1G ), and calcium and integrin family member 2 gene ( CIB2 or USH1J ). Although always severe, the course of disease may vary according to the type of variant.

Usher syndrome type 2: later-onset retinal degeneration in a deaf child

Congenital mild to severe sensorineural stable hearing loss with major impairment in high frequencies and normal vestibular function are the main characteristics of USH2. The retinal degeneration occurs later than in USH1, usually during or after puberty. USH2 and USH3 are not usually symptomatic in the first decade and initially have a normal fundus appearance. Many patients retain good visual acuity in spite of constricted visual fields. The ERG may initially be normal; however, ERG changes may be detected in pre-symptomatic young children. During the second decade, night blindness and loss of peripheral vision become evident and inexorably progress ( Fig. 46.1D ). Three main genes have been identified: usherin ( USH2A , and is also a common cause of non-syndromic RP), G-protein coupled receptor 98 ( GPR98 also named ADGRV1 , VLGR1 , USH2B or USH2C ), and whirlin ( WHRN , also named USH2D ) (NB: in addition PDZD7 has been named as as a modifier).

Usher syndrome type 3: the later-onset, variable form

The onset of RP in USH3 is variable and is often recognized after the second decade of life, but can be confused with the two other types. Sensory hearing loss is postlingual after the acquisition of speech (as opposed to the prelingual loss in USH1 and USH2), but it evolves progressively to profound deafness. Vestibular dysfunction of variable intensity occurs in half of the patients. Usher type 3 is mostly due to pathogenic variants in the clarin 1 gene ( CLRN1 , also named UHS3A ), particularly in Ashkenazi Jews and Finns. Much rarer biallelic pathogenic variants were found in HRAS1 (USH3B) in Amish families.

Pathogenesis of Usher syndromes

Progress has been made in understanding the pathogenesis of this disease, which affects the stereocilia of the inner ear and photoreceptor cells of the retina. Overall, 10 genes are implicated at the present time. The USH1 gene products form a network, the Usher interactome, which plays a key role in the early hair bundle development. They are also key components of the mechanoelectrical transduction machinery necessary for hearing. In the retina, the Usher interactome acts at the level of the ciliary/periciliary region of the connecting cilia of the photoreceptor cells. These are important for the transport of proteins between the outer and the inner segments. Alteration of the USH proteins leads to early dysfunction of the inner ear and of the retina simultaneously ( Fig. 46.1E ).

In addition to Usher syndrome, other syndromic non-Usher retinal dystrophies with deafness as main symptoms can occur in childhood such as: autosomal dominant Leber congenital amaurosis with early-onset deafness with variants in the TUBB4B gene, autosomal recessive cone rod dystrophy, and hearing loss with variants in the CEP250 gene.

The ciliopathies: a growing systemic retinal dystrophies group

A single non-motile cilium (“primary cilium”) is present in almost every vertebrate cell; motile cilia are present only in specific organs such as in the respiratory or the reproductive systems (for review see Brown et al. ) ( Fig. 46.2A ). The primary cilium is the central “antenna” of the cell, allowing transduction of sensorial information from the extracellular environment to the cell. The photoreceptor cell has a connecting cilium and is, therefore, a ciliated cell.

Fig. 46.2, Ciliopathies. (A) Schematic representation of cilia in various cells in the human. In green: motile cilia; in red: primary cilia. Continued overleaf.Fig. 46.2, cont’d (B) Schematic representation as an abacus (adding various target organs) of syndromes recognized as ciliopathies.

Ciliopathies are rare genetic disorders characterized by primary cilium dysfunction, frequently affecting photoreceptors and causing retinal degeneration either as an isolated condition (e.g. Leber congenital amaurosis with CEP290 mutations) or as a ciliopathy syndrome affecting more than one organ system. Ciliopathies involve many target organs that have in common an important role of the primary cilia. Overlapping phenotypes have been reported, as well as great clinical variability in the number and degree of severity of affected organs among patients with the same syndrome. The most common ciliopathies are schematically represented in Fig. 46.2B .

Molecular investigations have revealed major genetic heterogeneity for each syndrome and also allelic variability (different mutations in the same gene may lead to different syndromes). For instance, CEP290 – NPHP6 truncating variants have been identified in Joubert syndrome and hypomorphic variants in Leber congenital amaurosis (LCA). Moreover, CEP290 – NPHP6 is also mutated in several distinct disorders (nephronophthisis, Senior–Løken syndrome, Joubert syndrome, BBS, and the lethal Meckel syndrome).

Supplementary genetic factors such as a third mutated allele in a BBS gene (known as oligogenism – a third pathogenic variant occurring in addition to the two main variants found in recessive inheritance) or other genetic modifiers can influence the phenotype.

Annual multidisciplinary follow-up is recommended for these children, paying special attention to renal function, endocrine status, and prevention of obesity.

Bardet–Biedl syndrome

The cardinal features of the Bardet–Biedl syndrome (BBS) are early-onset retinal degeneration, polydactyly, obesity, renal dysfunction, and hypogonadism ( Fig. 46.3A–D ). Secondary features may include intellectual disability, anosmia, diabetes, cardiac anomalies, hepatic fibrosis, brachydactyly, and Hirschprung disease. The retinal dystrophy is early in onset, and leads to severe visual handicap before adulthood. Profound ERG abnormalities can be detected as early as 3 years of age but may occur later. Legal blindness usually results before the second decade of life. Retinal dystrophies in BBS are mainly a rod–cone dystrophy or a cone–rod dystrophy, usually classified as a global retinal degeneration because both rods and cones are affected ( Fig. 46.3E ).

Obesity is the second major feature, present in 72%–96% of BBS patients. It usually begins in early childhood and becomes increasingly severe with age. Its origin is both central (hypothalamic eating control) and peripheral (adipose tissue).

Limb anomalies are found in almost 95% of BBS patients, usually a postaxial polydactyly (69%). Other limb malformations such as brachydactyly or syndactyly are frequently reported for both hands and feet and have a diagnostic value. Abnormalities of the genitalia can occur: hypogonadism in males or vaginal atresia in females. Rarely, there is hydrometrocolpos, a neonatal vaginal malformation leading to a massive abdominal tumor. Renal dysfunction can occur in late childhood and may lead to kidney failure. Neuropsychiatric symptoms can include developmental delay, intellectual disability, learning difficulties, speech deficit, and behavioral problems. Intellectual function ranges from severe intellectual disability through low intelligence to normal intelligence. Slow ideation and hyperemotive status are common.

BBS is an autosomal recessive heterogeneous condition; more than 24 genes have been identified, which account for the molecular diagnosis of about 85% of cases.

All the genes have been related to cilium biogenesis and/or function. BBS1 and BBS10 are the two most common, each accounting for about 20% of the cases. Implication of the other BBS genes ranges from a unique family to a few percent of mutated families. The classical autosomal recessive inheritance model has been challenged by molecular and functional investigations with the oligogenic model and the effect of additional genetic modulators on the phenotype.

Alström syndrome

Alström syndrome (ALMS) manifestations include retinal degeneration in early childhood, sensory hearing impairment, and metabolic defects leading to insulin resistance with type 2 diabetes mellitus and obesity in childhood. Polydactyly does not occur. Cardiomyopathy can occur in infancy within the first months of life that can be recurrent or appear de novo with juvenile or adult onset that may lead to congestive heart failure. Renal dysfunction is reported in half of ALMS cases. Developmental or motor delay can occur (46%).

The first manifestation of ALMS is severe early-onset cone–rod retinal dystrophy, sometimes mimicking Leber congenital amaurosis with very early visual impairment, intense photophobia, and nystagmus ( Fig. 46.4 ). Children usually become truncally obese during their first year. Sensorineural hearing loss presents in the first decade in up to 70%; it may progress to the moderately severe range (40–70 dB) by the end of the first to second decade. Insulin-resistant type 2 diabetes mellitus often presents in the second decade and is accompanied by acanthosis nigricans (pigmentation mostly in body folds). Other endocrine and metabolic abnormalities include hypothyroidism, diabetes insipidus, dyslipidemia, growth hormone deficiency, hyperuricemia, hyperlipidemia, hypothyroidism, and hypogonadotrophic hypogonadism. Hepatic and renal dysfunction can be present in the second decade. Restrictive lung disease may represent a high risk during anesthesia. This syndrome requires a multidisciplinary follow-up to detect complications once the diagnosis is confirmed.

Fig. 46.4, Alström syndrome. (A) This 26-month-old girl was noted to be photophobic and overweight. She has pathogenic variants in the ALS gene. (B) Fundus photograph of the patient's macular region showing marked irregularity of the macula. Electroretinogram shows severe photopic reduction and a lesser degree of scotopic impairment. (C) Photograph of the peripheral retina; it is thinned with patchy pigmentation.

A single gene is involved in all the cases, ALMS1 , in which mainly nonsense and frame shift mutations occur (96%). ALMS1 protein has been found to be located at the base of cilia, however the precise pathogenesis remains to be determined.

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