Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Eye and Systemic Disease_Wright, Spiegel, Thompson_2006
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Sensorineural hearing loss occurs in about half of CS patients.90 Dental complications (especially severe caries) are common. Photosensitive dermatitis is present in two-thirds of the patients with CS. Thin, dry, scaly skin with diminished adipose tissue, thin hair, and sunken eyes are responsible for the “aged” appearance of patients with CS.128 Various renal complications, including renal vascular hypertension and structural anomalies of the kidneys, have been observed in about 10% of all reported cases.74 In male patients, cryptorchidism and micropenis may be present. Females with CS may develop irregular menstrual cycles. Patients with CS have a characteristic appearance with kyphosis and progressive hip, knee, and ankle contractures.
CS is clearly a disorder with variability in type and severity of symptoms. The average age of death is about 12 years.128 An early-onset “severe form” of CS has been reported in a subset of patients.148 Cataracts noted at birth or within the first 3 years of life are a poor prognosticator in CS. Nance and Berry noted that only 2 of 22 reported cases of CS with cataracts less than 3 years old survived beyond the age of 7.128
In the differential diagnosis one must consider other conditions such as progeria (Hutchinson–Gilford syndrome), Werner syndrome, cerebro-oculo-facial syndrome, and Pena–Shokeir II syndrome.91 The differential diagnosis for the pigmentary retinopathy seen with early neurological demise includes Pelizaeus–Merzbacher syndrome, Refsum’s disease, and ceroid lipofuscinosis.
Inheritance
Inheritance is autosomal recessive. Parents should receive genetic counseling regarding the 25% risk of subsequent affected children.
Treatment
The management of CS is purely symptomatic.
Prognosis
The prognosis is poor, with an average lifespan of 12 years.
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Kabuki Make-Up Syndrome
Kabuki make-up syndrome (KMS), also known as Niikawa–Kuroki syndrome, was first described in 1981,134 and is a multiple congenital anomalies/mental retardation (MCA/ MR) syndrome characterized by a peculiar face (100%), dermatoglyphic abnormalities (93%), skeletal anomalies (92%), mental retardation (92%), and postnatal growth retardation (83%).105,134 The name of the syndrome comes from the fact that the face of these patients resembles the mask used in the traditional Japanese “Kabuki” theater. More than 70 Japanese individuals and 100 non-Japanese individuals with this syndrome have been reported.189,205
Etiology
The etiology of KMS is unknown.
Clinical Features
The ophthalmic features diagnostic for KMS are long palpebral fissures, eversion of the lower eyelids, and laterally sparse, arched eyebrows (Fig. 8-6). The phenotype evolves over time, making the diagnosis difficult in infancy.19 Ptosis, strabismus,28 long eyelashes, epicanthal folds, hypotelorism,67 cataracts,145 blue sclerae, and uveitis22 have all been reported.
Systemic Associations
Other facial features include a broad and depressed nasal tip, prominent and broad philtrum, malar hypoplasia, cup-shaped ears with large prominent earlobes, preauricular dimples, and a low posterior hairline. Patients with KMS commonly have retromicrognathia, cleft or high arched palate, deficient dentition, and widely spaced teeth.67 The open mouth with tented upper lip gives a myopathic facial appearance to KMS patients.
Various skeletal abnormalities are prevalent in patients with KMS. Radiologic abnormalities include spinal deformities, sagittal cleft of the vertebrae, curved fifth fingers, and stubby short fingers (brachydactyly). Joint laxity and joint dislocations (hips, patella) have been reported in connection with KMS.19,22 Other unusual findings in KMS include the persistence of fingertip pads, atypical dermatoglyphic pattern of the fingers and palms,
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FIGURE 8-6. Child with Kabuki make-up syndrome. Note the long palpebral fissures, eversion of the lateral portion of the lower eyelids, arching eyebrows, strabismus, and protruding ears. (Courtesy of Dr. G.S. Oliveira, Campinas, Brazil.)
a simian crease, and an excess of the ulnar loop patterns on fingers.67
Among patients with KMS, recurrent otitis media is quite common. Igawa and associates demonstrated middle and inner ear malformations including hypodysplasia of the cochlea, vestibule, and semicircular canal with subsequent hearing deficits. Computerized tomography (CT) of the petrous bone and audiometry should be performed during early infancy in patients with KMS to optimize rehabilitation of the affected individuals.82
The primary manifestation of the CNS is microcephaly.19,105,133 Structural CNS defects have been reported (arachnoid cyst,28 ventriculomegaly93). Mental retardation is present in more than two-thirds of the patients. The mean developmental quotient is 52 in children and 62 in older patients. Severe mental retardation is uncommon. Occasional individuals have had normal intelligence.93
Postnatal growth deficiency usually manifests within the first year of life and becomes more obvious with advancing age.
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Mean height in children 12 months and over is 2 standard deviations below average.93
In addition to the cardinal features of KMS, about 50% of the patients have congenital heart defects. Malformations associated with altered hemodynamics can occur, and include coarctation of the aorta, bicuspid aortic valve, mitral valve prolapse, membranous ventricular septal defect, pulmonary, aortic, mitral valve stenosis, tetralogy of Fallot, single ventricle with common atrium, double-outlet right ventricle, and transposition of the great vessels.133
Inheritance
Most patients with KMS represent a new mutation.133 There are, however, a few examples of familial KMS cases in the medical literature. KMS in these families shows an autosomal dominant inheritance pattern with a variable expressivity.67,171,190
OPITZ G/BBB SYNDROME
Opitz G/BBB syndrome was first described in 1969 as two separate disorders, the G syndrome and the BBB syndrome.140,141 The G syndrome, also known as Opitz–Frias syndrome, was characterized by ventral midline defects including hypertelorism, hypospadias, cleft lip and palate, and laryngo-tracheo-esophageal defects. The BBB syndrome was characterized by hypertelorism and hypospadias in males, with affected females having only hypertelorism. It has become clear that the BBB and G syndromes are in fact one entity, now named the Opitz G/BBB syndrome.129
Etiology
See Heredity section.
Clinical Features and Systemic Associations
Wide clinical variability, ranging from neonatal lethality to an asymptomatic form, has been well described in Optiz G/BBB, making diagnosis difficult in mild cases.138 The most striking features of Optiz G/BBB are the facial manifestations, which may include ocular hypertelorism, telecanthus, upward or
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downward slanting palpebral fissures and epicanthal folds, broad nasal bridge with anteverted nostrils, cleft lip with or without cleft palate, short frenulum of the tongue, micrognathia, posterior rotation of the auricles, and widow’s peak (Fig. 8-7).94 Occasionally, bifid uvula, cleft tongue, dental anomalies, and ankyloglossia are observed in patients with Optiz G/BBB.16
Severe abnormalities may involve tracheo-esophageal- laryngeal cleft or fistula formation, and neuromuscular defects of the esophagus, leading to chronic dysphagia, regurgitation, and aspiration pneumonia. Although males tend to have more severe and more frequent laryngoesophageal defects, it is important to recognize that this disorder can express itself in both males and females with equal severity. Infants classically
FIGURE 8-7. Face of a boy with Opitz (G/BBB) syndrome. Note hypertelorism, telecanthus, broad nasal bridge, and ptosis (right eye).
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present with a weak, hoarse cry and stridor. Mildly affected patients may only manifest functional swallowing impairment, which improves with age.80 Initial failure to thrive is followed by normal growth in survivors.94 Frequently, patients with Optiz G/BBB have ectopic or imperforated anus.16 Patients with Optiz G/BBB often have mild to moderate mental retardation.
A variety of midline brain anomalies including absence of corpus callosum, wide septum pellucidum, cerebellar vermal hypoplasia, and large cisterna magna have been described among those Optiz G/BBB patients who have had imaging studies.118 The most common cardiac defects encountered are conotruncal lesions and have been observed in a subset of patients with Optiz G/BBB.94
In the differential diagnosis of Optiz G/BBB, one must consider Aarskog syndrome, Robinow’s syndrome, and frontonasal dysplasia sequence. Individuals affected with Aarskog syndrome and Robinow’s syndrome have abnormally wide-set eyes and midline facial and genital anomalies, but individuals affected with frontonasal dysplasia sequence have facial anomalies involving the midline but do not have genital anomalies.
Inheritance
Opitz syndrome (Optiz G/BBB) is a heterogeneous condition with both autosomal dominant and X-linked transmission.119,176 Clinically indistinguishable forms have been mapped to Xp22 and to 22q11.2.155 Based on clinical data, it appears that Optiz G/BBB is a condition distinct from DiGeorge/velo-cardio-facial (DGS/VCFS), which has also been mapped to 22q11.2. There is, however, some overlap among these conditions, especially in regard to the types of congenital heart defects.156 The candidate gene at the Xp22.3 locus is called MID1. The transcript of this gene has been found in virtually all normal fetal tissues. No transcripts were detected however, in samples from affected males with Optiz G/BBB. The MID1 gene encodes a protein called midin, whose function is predicted to be important for development of midline structures.167
Prognosis
Progosis is highly variable because of the wide range of clinical severity.
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PRADER–WILLI SYNDROME
In 1956, Prader, Labhart, and Willi described what has come to be known as Prader–Willi syndrome (PWS).152 Also known as the Prader–Labhart–Willi syndrome, it is the most common dysmorphic form of human obesity (Fig. 8-8). The prevalence of PWS is estimated to be 1 in 15,000, with an incidence ranging from 1 in 16,000 to 1 in 25,000 births.87
Etiology
Prader–Willi syndrome is caused by a defect in the region of chromosome 15q11–q13 (see Inheritance section).
Clinical Features and Systemic Associations
Criteria for the clinical diagnosis of PWS were established in 1993, and include obesity, short stature, small hands and feet, hypotonia in infancy, hypogonadism, and mental retardation (Fig. 8-8).77 Although several of the clinical features and endocrine abnormalities associated with PWS suggest a hypothalamic problem, examinations of the hypothalamus and pituitary gland by routine methods have failed to show pathological lesions.13
The ocular manifestations of Prader–Willi syndrome (PWS) include strabismus, almond-shaped eyes, and hypopigmentation of the uvea. Fifty percent to 95% of patients with PWS have strabismus,5,25,73 with esotropia being the most common form of strabismus (Hered). Myopia is another relatively common finding, observed in 15% to 40% of PWS children.25,73 Bilateral cataracts have been described, and may be associated with a metabolic etiology (an abnormal glucose tolerance test).198 Telecanthus,158 nystagmus,38 nonspecific visual field defects, optic atrophy, congenital ectropion uveae, and glaucoma have been reported.56
Creel et al. reported an abnormal VEP in three of six patients tested with PWS.38 The finding of VEP asymmetry typically seen in albinism has not been replicated in subsequent series when VEPs were conducted on known PWS patients.158 A likely explanation for this discrepancy is that the p gene, which is important to normal pigmentation in humans and is the site for the most common form of albinism (OCA2), also contains the critical, distinct regions for the PWS and Angelman’s syndrome.
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FIGURE 8-8. A 15-year-old boy with Prader–Willi syndrome. Note short stature, truncal obesity, small hands and feet, and typical facial features, including narrow bifrontal diameter and almond-shaped eyes.
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Thus, a subset of patients with PWS and Angelman’s also have OCA2.14
Characteristic facial features of PWS include almond-shaped appearance of palpebral fissures, which may be upslanting, narrow bifrontal diameter of the head, and thin upper lip.87 Decrease in hand width with straight ulnar border is unique in PWS.77 Fairer skin and lighter hair compared to other family members is present in about 50% of patients. Most hypopigmented children have a cytogenetic deletion.20
A typical pattern of growth has been demonstrated in PWS: normal length at birth, deceleration of linear growth during the first few months of life, relatively steady length growth during childhood, and falloff in growth in adolescence. Mean adult height is 155 cm for males ( 3rd centile) and 147 cm for females ( 3rd centile).21
Fetal and neonatal hypotonia, feeding problems, and failure to thrive in the newborn period are the earliest clinical features of PWS. Excessive weight gain follows the period of failure to thrive in early infancy in PWS. The onset of obesity is from 6 months to 6 years.87 An increased caloric intake and decreased caloric expenditure are believed to account for the obesity. Diabetes mellitus is seen in patients with PWS and is probably related to the obesity. Children younger than 6 years of age show delayed motor, cognitive, and language development. Mental retardation is mild in 63%, moderate in 31%, and severe in the rest of PWS patients.39
A peculiar feature of PWS is the common presence of thick viscous saliva, which tends to crust at the corners of the mouth. A high threshold for vomiting is another odd, unexplained observation in many individuals with PWS.77 Food-related behavior problems, including excessive appetite and an absent sense of satiation, are typical. Excessive daytime sleeping frequently occurs in older children and adults with PWS.24 Sleep apnea may be obstructive or central or both.
The manifestations of hypogonadism vary in both sexes in PWS. The extent of sexual maturation is variable in PWS patients who are not treated with hormones.87
Patients with PWS are frequently described as stubborn. Verbal perseverance on favorite topics is one of the most common annoying behavioral features in PWS. Self-mutilating habits, especially picking at minor skin lesions, are common behaviors in older children with PWS. People with PWS have surprisingly high pain tolerances.77 In many individuals with
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PWS, strong visual-perceptional-motor skills have been documented. This exceptional skill may explain the proficiency of PWS patients with jigsaw puzzles.77
Early feeding difficulties may require alternative feeding regimens, such as gavage or even gastrostomy.13 Life-threatening obesity was once thought inevitable and incurable in PWS. However, lowering caloric intake in persons with this syndrome has been successful.78
Inheritance
The PWS is caused by absence of a paternal contribution of the chromosome region 15q11–q13, resulting from paternal deletions (70%), maternal uniparental disomy (i.e., two maternal copies and no paternal copies of 15q), or rare imprinting mutations.48,106,130 The deletion of the long arm of chromosome 15 at q11–q13 is detectable with either high-resolution chromosomal analysis or fluorescent in situ hybridization (FISH) using specific probes. In an individual patient with relatively certain clinical diagnosis of PWS, FISH analysis may be the most efficient diagnostic test, as approximately 70% of patients will have a deletion detectable by FISH.61
In cases where the diagnosis is in question, methylation analysis is the most efficient single test for ruling out a PWS diagnosis. Conventional cytogenetic analysis in parallel with methylation studies is advised to detect rare chromosomal translocation cases and also to detect other chromosomal abnormalities in patients who do not prove to have PWS.61
PROTEUS SYNDROME
The Proteus syndrome (PS) is a rare congenital hamartoneoplastic disorder, with markedly variable clinical expression, in which several systems are involved in an apparently haphazard process of overgrowth (Fig. 8-9). Cohen and Hayden were the first to delineate Proteus syndrome in 1979.34 It has been suggested that Joseph Merrick, the Elephant Man, most likely had PS.32 Fewer than 100 cases of PS have been recorded to date.
Etiology
Recent reports have suggested that this disorder results from a somatic alteration of a gene leading to mosaic effects that