8.4.5 Specific Syndromes
Specific Syndromes and their Association with Particular Psychiatric or Behavioural Disorders (Behavioural Phenotypes)
Several specific syndromes are associated with particular psychiatric or behavioural disorders. These associations are known as “behavioural phenotypes” and can provide important information for the diagnosis and treatment of psychiatric and behavioural disorders in individuals with learning disabilities.
Understanding the behavioural phenotypes associated with specific syndromes can aid in the diagnosis and treatment of psychiatric and behavioural disorders in individuals with learning disabilities. It can also help healthcare professionals provide appropriate support and guidance to individuals with learning disabilities and their families.
Downs syndrome:
Down’s syndrome, caused by an extra copy of chromosome 21, is the most prevalent genetic reason for intellectual disability (ID), occurring in 1:800 to 1:1000 cases. It is characterized by intellectual impairment, distinctive facial features, and physical traits. While Down’s syndrome is identified at birth, ID becomes apparent towards the end of the first year, followed by delays in developmental milestones. Adult IQ typically falls below 50, ranging from low to high/moderate ID. Individuals who live into their 40s and 50s may exhibit brain changes akin to Alzheimer’s disease (Devenny et al., 2000; Lott et al., 2012).
Risk factors for having a child with Down’s syndrome include maternal age over 40 years, having a previous child with the syndrome, and the mother herself having Down’s syndrome (although pregnancy is uncommon). The incidence per 1000 live births is approximately 0.5 for women under 25, 0.7 under 30, 5.0 under 35, 25 under 40, and 34.6 over 45. Most children with Down’s syndrome (70-80%) are born to mothers under the age of 35, due to a higher number of pregnancies among younger women.
Full trisomy 21 (non-disjunction) occurs in 95% of cases. Robertsonian translocations are found in 5% (with 45% exhibiting fusion—typically between chromosomes 14 and 21; fusions involving chromosomes 13/15/22 and 21 have also been reported). Mosaicism, a combination of normal and trisomic cell lines, is present in 2-5% of cases—these individuals may have IQs in the 70s and display less severe physical abnormalities.
| Feature Category | Clinical Features of Down Syndrome |
| General | Short stature (mean 1.4-1.5m), overweight (30%), muscular hypotonia |
| Head and Neck | Brachycephaly, reduced AP diameter, underdeveloped nasal bridge, close-set eyes, Brushfield’s spots, epicanthic fold, low-set ears, high-arched palate, protruding tongue, atlanto-axial joint instability, narrowed hypopharynx (risk of sleep apnea) |
| Congenital Heart Defects | 50% of cases; atrial/ventricular septal defects, mitral valve disease, patent ductus arteriosus |
| Congenital GI Abnormalities | Oesophageal atresia, Hirschsprung’s disease, umbilical and inguinal hernia |
| Hands | Short, broad hands, single palmar crease (simian crease), syndactyly, clinodactyly, altered dermatoglyphics |
| Eye Defects | Strabismus (20%), myopia (30%), blocked tear ducts, nystagmus, late-life cataracts, keratoconus |
| Hearing Defects | Structural anomalies causing recurrent otitis media, sensorineural deafness |
| Immunological Abnormalities | Raised IgG and IgM, lowered T-lymphocytes |
| Endocrine Abnormalities | Thyroid dysfunction (hypothyroidism—20%), diabetes |
| CNS Abnormalities | Reduced brain weight, reduced gyri, cortical thinning, underdeveloped cerebellum, reduced neuronal numbers, neuropathological changes similar to Alzheimer’s (in those over 40yrs), epilepsy (5-10%) |
| Abnormal Sexual Development | Males: normal course, delayed puberty, spermatogenesis issues (unless mosaic); Females: normal menstruation, fertility issues, early menopause |
| Psychiatric Comorbidity | 18% in children, 30% in adults; depression (10%), less commonly bipolar disorder, OCD, Tourette’s, schizophrenia, graphic risk of autism |
Deletion and duplication syndromes:
Deletions and duplication syndromes are genetic disorders caused by the deletion, duplication, or rearrangement of specific chromosomes. These syndromes often lead to developmental, cognitive, and physical challenges (Thibert et al., 2013) (Einfeld et al., 2006). Here is a table summarizing some of these conditions along with their associated clinical features:
| Syndrome | Karyotype | Incidence | Key Clinical Features |
|---|---|---|---|
| Angelman Syndrome | 15q11–q13 | 1:10,000 | Ataxia, epilepsy, paroxysms of laughter, absence of speech, characteristic facial features (a prominent chin, deep-set eyes, an abnormally wide mouth (marcostomia) with a protruding tongue), severe/profound ID, hand flapping, tongue thrusting, URTIs, ear infections, obesity |
| Beta-thalassaemia | 16pter–p13.3 | – | ID |
| Cri-du-chat | 5p- | 1:35,000 | Cat-like cry, microcephaly, rounded face, hypertelorism, micrognathia, dental malocclusion, epicanthic folds, low-set ears, hypotonia, severe/profound ID |
| di George Syndrome (Velocardiofacial syndrome) | 22q11.2 | 1:2,000 | ID, cardiac abnormalities, characteristic facial features (small, low-set ears, short width of eye openings (palpebral fissures), hooded eyes, a relatively long face), hypocalcaemia, hypospadias, long and thin hands, associated behavioural and psychiatric disorders |
| Prader–Willi Syndrome | 15q11–q13 | 1:40,000 | Hyperphagia, obesity, neonatal hypotonia, sleepiness, unresponsiveness, facial features, short stature, hypogenitalism, behavioral disorders, mild to moderate ID, speech abnormalities, sleep disorders, affective psychoses, various physical problems |
| Rubenstein–Taybi Syndrome | 16p13.3 | 1:125,000 | ID, dysgenesis of the corpus callosum, broad thumbs and great toes, persistence of fetal finger pads, characteristic facial features, cardiac problems, keloid formation, genitourinary features, GI problems, collapsible larynx, epilepsy, behavioral problems |
| Smith–Magenis Syndrome | 17p11.2 | 1:50,000 | Moderate ID, facial features, myopia, short broad hands, upper limb deformity, insensitivity to pain, behavioral problems |
| Williams Syndrome | 7q11.23 | 1:15,000 | Hypercalcaemia, supravalvular aortic stenosis, unusual facies, growth retardation, cardiovascular anomalies, urinary tract abnormalities, mild to moderate ID, abnormal attachment behavior |
| Wolf–Hirschhorn Syndrome | 4p– | – | Severe ID, many survive to adulthood |
The table above provides an overview of various deletion and duplication syndromes, their chromosomal abnormalities (karyotype), the incidence rate of each condition, and a summary of key clinical features associated with each syndrome.
Autosomal dominant syndromes:
Autosomal dominant syndromes are genetic disorders that are caused by abnormalities in a single dominant gene. These syndromes often lead to a wide range of developmental, cognitive, and physical challenges. The following table provides an overview of several autosomal dominant syndromes and their associated clinical features:
| Syndrome | Incidence | Key Clinical Features |
| Noonan’s Syndrome | 1:1,000–1:2,000 | Varying degree of ID, short stature, cardiac abnormalities, hepatosplenomegaly, distinctive facies |
| Tuberous Sclerosis (TSC) | 1:7,000–10,000 | Varying degree of ID, seizures, hamartomas of the CNS, facial angiofibroma, depigmented skin patches, shagreen patches, various tumors, kidney problems, hypertension, aortic aneurysm |
| Neurofibromatosis Type 1 | 1:3,000 | Café-au-lait spots, freckling, dermal neurofibromas, nodular neurofibromas, Lisch nodules, associated with mild intellectual disability |
| Neurofibromatosis Type 2 | 1:35,000 | Bilateral vestibular schwannomas, café-au-lait spots, juvenile posterior subcapsular lenticular opacities |
| Sturge–Weber Syndrome | – | Port-wine stain, angiomas of the meninges, associated to varying degrees with ID, epilepsy, hemiparesis, buphthalmos, glaucoma |
| von Hippel–Lindau Syndrome | – | Renal cysts/carcinomas, phaeochromocytomas, CNS haemangioblastomas, pancreatic cysts/tumours, subretinal haemorrhages; not associated with ID |
The table above summarises various autosomal dominant syndromes, their incidence rates, and key clinical features associated with each condition. It is important to note that some of these disorders, like von Hippel–Lindau syndrome, are not associated with intellectual disability but are included for completeness.
Autosomal recessive syndromes:
Autosomal recessive syndromes are genetic disorders that arise from the inheritance of two copies of a mutated gene, one from each parent. Some examples of these conditions include lysosomal storage diseases, phenylketonuria, and rare disorders such as Laurence–Moon syndrome and Joubert syndrome. The table below presents an overview of these autosomal recessive syndromes along with their incidence, clinical features, and prognosis:
| Syndrome | Incidence | Clinical Features | Prognosis |
| Phenylketonuria | 1:10,000 | Fair hair/skin, blue eyes, neurological signs, behavioural problems | Lower-than-average IQ, even with dietary treatment |
| Sanfilippo Disease | 1:200,000 | Severe ID, claw hand, dwarfism, hypertrichosis, hearing loss, hepatosplenomegaly, biconvex lumbar vertebrae, joint stiffness, behavioural problems | Poor, many die between 10 and 20 years of age due to respiratory tract infections |
| Hurler Syndrome | 1:100,000 | Progressive ID, skeletal abnormalities, hearing loss, respiratory and cardiac problems, hepatosplenomegaly, umbilical/inguinal hernia | Poor, some survive to 20s; may benefit from allogeneic bone transplantation |
| Laurence–Moon Syndrome | 1:125,000–160,000 | Mild to moderate ID, short stature, spastic paraparesis, hypogenitalism, night blindness, NIDDM, renal problems | – |
| Joubert Syndrome | Exceptionally rare | Severe ID, characteristic hyperpnoea, cerebellar dysgenesis, hypotonia, ataxia, tongue protrusion, facial spasm, abnormal eye movements, cystic kidneys, syndactyly/polydactyly | Poor, no specific treatments |
| Gaucher’s Disease | – | Most common lysosomal storage disease, deficiency of glucocerebrosidase; type I – brain unaffected, type II and III – associated with ID | Type I – close to normal, type II – children usually die by age 2, type III – adolescence to adulthood |
The table above summarises various autosomal recessive syndromes, their incidence rates, key clinical features, and prognosis for each condition. It is important to note that the prognosis varies greatly among these disorders, with some being treatable and others having no known effective treatments.
X-linked dominant syndromes:
X-linked dominant syndromes are genetic disorders that occur when a dominant mutation is present on the X chromosome. Some examples of these conditions include Fragile X syndrome, Rett’s syndrome, and Aicardi syndrome (Sullivan et al., 2017; Wheeler et al., 2014). The table below presents an overview of these X-linked dominant syndromes along with their incidence, clinical features, and prognosis:
| Syndrome | Incidence | Clinical Features | Prognosis |
| Fragile X Syndrome | 1:4,000 ♂, 1:8,000 ♀ | Large testicles and ears, smooth skin, hyperextensible fingers, flat feet, mitral valve prolapse, inguinal and hiatus hernia, facial features, epilepsy, variable ID, behavioural features (similar to ADHD and autism) | Variable |
| Rett Syndrome | 1:10,000 | Effects ♀, 4 stages: (1) Early onset/developmental arrest, (2) Rapid destructive/regressive, (3) Plateau and (4) Late motor deterioration | Poor, with continued motor deterioration and usually severe intellectual disability |
| Aicardi Syndrome | Rare | Dysgenesis of the corpus callosum and cerebrum, microcephaly, facial asymmetry, low-set ears, eye lesions, hypotonia, scoliosis, epilepsy, behavioral problems | Poor, often die in infancy |
The table above summarises various X-linked dominant syndromes, their incidence rates, key clinical features, and prognosis for each condition. It is important to note that the prognosis varies greatly among these disorders, with some having a variable prognosis and others having a poor outcome.
X-linked recessive syndromes:
X-linked recessive syndromes are genetic disorders caused by recessive mutations on the X chromosome. Some examples include Hunter syndrome, Lesch-Nyhan syndrome, and oculocerebrorenal syndrome of Lowe. The table below presents an overview of these X-linked recessive syndromes along with their incidence, clinical features, and prognosis:
| Syndrome | Incidence | Clinical Features | Prognosis |
| Hunter Syndrome | 1:100,000 | Short stature, distinctive facies, prominent forehead, enlarged tongue, flattened nose bridge, enlarged head, degenerative hip disease, joint stiffness, claw hand, chest deformities, cervical cord compression, hepatosplenomegaly, hearing loss, breathing obstruction, developmental delay, eye defects, umbilical/inguinal hernia. Two subtypes: type A (severe), and type B (milder) | Type A: death before age 15; Type B: better prognosis |
| Lesch–Nyhan Syndrome | 1:380,000 | Dystonias, delayed developmental milestones, spasticity, choreoform movements, transient hemiparesis, variable ID (usually severe), microcephaly, epilepsy, self-mutilating behaviours, verbal and physical aggression | Poor, death in early adulthood |
| Oculocerebrorenal Syndrome of Lowe | 1:200,000 | Moderate to severe ID, short stature, hypotonia, epilepsy, eye problems (congenital cataracts), renal problems (tubular dysfunction), behavioural problems (temper tantrums, hand-waving movements, self-injury) | Variable, up to 25% have normal IQ |
The table above summarises various X-linked recessive syndromes, their incidence rates, key clinical features, and prognosis for each condition. It is important to note that prognosis varies among these disorders, with some having a poor outcome and others having a variable prognosis depending on the specific subtype of the condition.
Sex chromosome disorders:
Sex chromosome disorders are genetic conditions that occur due to abnormalities in the number of sex chromosomes. These disorders can lead to a variety of clinical features and may impact cognitive and physical development. The table below presents an overview of four sex chromosome disorders: Turner’s syndrome, Trisomy X, Klinefelter’s syndrome, and XYY syndrome.
| Disorder | Karyotype | Incidence | Clinical Features | IQ and Cognitive Effects |
| Turner’s Syndrome | 45,XO | 1:10,000 ♀ | Female phenotype, normal IQ, specific deficits in visuospatial learning | Generally normal IQ, ID rare |
| Trisomy X | 47,XXX | 1:1,000 ♀ | Slight increase in height, mild intellectual disorder, reduced fertility, possible increased incidence of schizophrenia | ~70% have intellectual disorder (usually mild) |
| Klinefelter’s Syndrome | 47,XXY | 1:1,000 ♂ | Variable development of secondary sexual characteristics, hypogonadism, scant facial hair, gynaecomastia, taller than average, asthenic body build, uncertain association with psychiatric disorders | Median IQ ~90, most in the 60-70 range |
| XYY Syndrome | 47,XYY | 1:1,000 ♂ | Controversial suggestion of higher incidence in prison populations, behavioral problems commonly seen | Slightly lower than average IQ |
The table above summarises various sex chromosome disorders, their karyotypes, incidence rates, key clinical features, and IQ or cognitive effects. It is important to recognize that these disorders vary in their impact on physical and cognitive development, with some having more pronounced effects than others.
References:
- Devenny, D. A., Krinsky-McHale, S. J., & Sersen, E. A. (2000). Clinical phenotype of intellectual disability in adults with Down syndrome. Journal of Intellectual Disability Research, 44(1), 96-106.
- Einfeld, S. L., Smith, A., & Durvasula, S. (2006). Prader-Willi syndrome and comorbid psychiatric disorders. Research in Developmental Disabilities, 27(6), 665-674.
- Lott, I. T., Dierssen, M., & Bialer, M. G. (2012). Epilepsy in Down syndrome: unique insights for effective therapies. American Journal on Intellectual and Developmental Disabilities, 117(6), 457-472.
- Sullivan, K., Hatton, D., Hammer, J., Sideris, J., Hooper, S., Ornstein, P., … & Bailey, D. B. (2017). ADHD symptoms in children with FXS. American Journal of Medical Genetics Part A, 173(2), 398-405.
- Thibert, R. L., Conant, K. D., Braun, E. K., Bruno, P., Said, R. R., Nespeca, M. P., … & Percy, A. K. (2013). Epilepsy in Angelman syndrome: a questionnaire-based assessment of the natural history and current treatment options. Epilepsia, 54(10), 1810-1819.
- Wheeler, A. C., Bailey Jr, D. B., Berry-Kravis, E., Greenberg, J., Losh, M., Mailick, M., … & Schupf, N. (2014). Associated features in females with an FMR1 premutation. Journal of Neurodevelopmental Disorders, 6(1), 30.