DYSGONOSOMIES AND RELATED SYNDROMES
A - TURNER SYNDROME
In a few words, Turner syndrome (or Ullrich-Turner syndrome) is a syndrome of growth retardation and impuberism with frequent cardiovascular or renal malformation, normal intelligence, due to a chromosome imbalance: 45, X and variants.
- I. Epidemiology:
- 0.4 /1000 female births (but 20 % of chromosome anomalies found in early miscarriages, i.e. about 10% early miscarriages).
- due to the loss of the maternal gonosome (a X) in 20-30% of cases, or of the paternal gonosome (a X or a Y) in the remaining 70-80%.
- II. Clinical ascertainment/examination:
The diagnosis can be evoked either:
- in the newborn (from dysmorphia and/or malformations), or:
- in the girl (from growth retardation, impuberism).
1 - neo-natal form:
- prenatal (and postnatal) growth retardation
- single umbilical artery frequently.
- Bonnevie-Ullrich (BU) status associating:
- lymphoedema of hands and feet (tough, non inflammatory, regressive at age 2 yrs).
- excess of skin and webbed skin on the nucha (pterygium colli).
1/3 of BU are found in Turner syndrome, and 75 % of Turner have a BU
In the presence of this symptomatology, a karyotype will be undertaken and (cardiac, renal) malformations will be searched for.
2 - in childhood or adolescence:
- small size (adult < 1,45 m).
- triangular shaped face, looks sad.
- possible epicanthus.
- downward slanting palpebrale fissures.
- short neck.
- pterygium colli in more than half cases.
- low hair line.
- high-arched palate.
- low set hears
- shield chest.
- widely spaced nipples.
- short 4th metacarpal.
- cubitus valgus (increased carrying angle of the elbow).
- radius curvus (Madelung's deformity).
- sinking of internal tibial plateau (sign of Kosowizc in the adult).
- osteoporosis (and fracture increased risk) above 45 yrs.
- multiple pigmented nevi; vitiligo and/or café-au-lait spots.
- risk of keloid scars (surgery only when needed, avoid plastic surgery).
- dermatoglyphics: number of digital crests = 187 - (30 * X) - (12 * Y) (herein = 157).
- hypoplastic nails
- infantile external genitalia.
- hypoplastic uterus.
- amenorrhea and sterility.
- absence of breast development.
- rare pubic pilosity.
- normal or subnormal intelligence; the (slight) cognitive defects are limited to visual-spatial/perceptual abilities, attention, motor function, and nonverbal memory. May be partly due to psycho-social suffering, but also to genetic imbalances and their various consequences (e.g. hormone deficiency).
- cardiovascular (20-30%): aortic coarctation (10-15 %) which may lead to death by dissection or rupture of the aorta; bicuspid aortic valve; left superior vena cava, and other malformations; in the presence of aortic coarctation in a girl, a Turner syndrome must be evoked.
- renal (40-50 %): horseshoe kidney, hydronephrosis...
- congenitally dislocated hip, scoliosis
- sense-organs: deafness (impaired hearing in up to 40%), myopia, cataract, strabismus.
- X linked recessive inherited traits have the same frequency in Turner syndrome and in the male, since they both have only 1 X; this frequency is that of the allele (e.g. daltonism, hemophilia, Duchenne de Boulogne myopathy...).
- III. Diagnosis: the karyotype:
- 45, X homogeneous: 55 % of cases.
- isochromosomes: i(Xp), i(Xq); deleted chromosomes: del (Xp), del (Xq); rings: r(x); mosaicisms... --> phenotypes are more or less evocative of Turner syndrome some patients having been fertile.
- most of the phenotypic traits are due to Xp deletion, and only ovarian failure is consistently associated with Xq deletions.
- IV. Assessments:
- ovarian failure (sex steroid deficiency and amenorrhea).
- streak gonads (germinal cells regress at the 3rd month in utero; biopsy is not needed).
- impaired glucose tolerance; hypertension (20-30%).
- autoimmune thyroid disease (T4, TSH, thyroid-antibody titer determinations).
- X-rays (skeleton, urinary system, heart).
- V- Differential diagnosis:
- other disorders with Bonnevie-Ullrich status.
- gonadic dysgenesia.
- other disorders with primary amenorrhea; e. g.: XY females (sex reversal).
- VI. Treatments:
- surgery of malformations.
- gonadectomy if a Y chromosome is present in mosaic (neoplastic risk).
- growth hormone and oestrogens to manage growth failure and to induce menarch and secondary sexual characters and menarche and to prevent osteoporosis.
- psychological support (sterility).
Comments: Genes implicated in the syndrome are thought to be localised in the region of the gonososomes which escape X inactivation; the various clinical manifestations may either be due to haploinsufficiency of specific genes (in the pseudoautosomal region of X), aneuploidy effects (e.g. on meiosis), and/or fetal suffering from the lymphoedema.
B - KLINEFELTER SYNDROME
In a few words, Klinefelter syndrome is a syndrome of a normal or gynecoid male with normal intelligence or mild retardation, infertility, and possible behaviour or psychiatric problems, due to a chromosome imbalance: 47, XXY and variants.
C - FRAXA and FRAXE SYNDROMES (Fragile Xq or fra(X)(q28))
- I. Epidemiology:
- FRAXA: 0.2 / 1 000 male births and 0.1 / 1 000 female births.
- FRAXE: 0.02/ 1 000 male births.
- II. Clinics:
- the face reminds of the one found in trisomy 8.
- high forehead.
- midface hypoplasia.
- large nasal root.
- thick lips.
- high palate.
- large, unfolded ears.
- fertility is often normal.
- III. Mental development and psychiatric behaviour (paragraph written by Denis Reserbat-Plantey):
- In the male:
- Mental retardation is mild to severe (mean IQ = 50): from a delay in school training to the impossibility to acquire writing and reading skills. The Fragile Xq young child is often hypotonic; in the more severe forms, a psychomotor delay is already present (delay in walking...).
- Speech difficulties: delay language appearance, dysarthria, omissions, mumblings, echolalias (tendency to repeat the same sentences and to ask the same questions).
- Behaviour problems: anguish, attention deficit, hyperactivity, impulsiveness, escape of glance, resistance to change, aggressiveness, self-mutilation, stereotypies (wings beating, "flapping") and oddities. Sometimes all these symptoms are present, and constitute an autistic syndrome.
- The various studies carried out among the autists show that 5 to 7 % autists are Fragile Xq.
- In the female:
The mental retardation is mild or absent. They can present with: school difficulties (less than in the boy), memory disorders, changing mood, timidity, relational difficulties, and depressive tendency. These symptoms are often misinterpreted for social causes.
- IV. Diagnosis: the karyotype can show recurrent gaps in Xq27-q28; however, the diagnosis now rely on the molecular study of the genes.
- The disease is due to the hyperexpansion of a CGG trinucleotide repeats in the 5' untranslated region of the gene FMR-1 (fragility, mental retardation), located in Xq27.3.
- As a consequence of their hyperexpansion, these CpG islands become hypermethylated, leading to shut down the FMR-1 gene expression.
- The normal FMR-1 product is a protein called FMRP, a RNA binding protein widely expressed, in particular in the brain and the testis
- In the normal population, the CGG repeat size is variable, from 6 to 54 repeats; it is inherited in a stable manner.
- Some people have between 60 and 200 repeats; this is called premutation; it is inherited in an unstable manner (you tend to have more repeats than Mummy), but stable in the individual (identical in each cell). Premutation carriers have a normal phenotype. Frequency of premutations in the population is 2.5/1000.
- Hyperexpansion of more than 200 repeats are called full mutation; they are hypermethylated (on cytosines; even on the active X); it is inherited in an unstable manner, but also, the mutation is unstable in the individual (somatic mutations). Almost all males and half of females with the full mutation exhibit the syndrome. It is milder in females.
- passage from the normal allele to premutation as never been observed.
- passage from premutation to mutation (unstability, or expansion through inheritance) is only through transmission from a female carrier.
D - 47, XXX
- Epidemiology: 1 / 1 000 female births; increased parental age.
- often undetected: a normal female with normal phenotype, puberty, fertility, and offspring (most often).
- precocious menopause.
- mild mental delay and/or psycho-social disturbances are sometimes found.
E - 48, XXXX and 49, XXXXX
- mimics trisomy 21; mental retardation.
F - 47, XYY
- Epidemiology: 1 / 1 000 male births.
- often undetected: a normal but tall male with a normal phenotype.
- fertility may be reduced; normal offspring.
- mild mental delay can be present; impulsivity,violence, and psychiatric behaviour are not rare.
G - XX MALE SYNDROME
- Epidemiology: 0.1 / 1 000 male births.
- Clinics: Klinefelter like phenotype; sterility.
- Sex reversal can be due to the presence of male determining sequences on a X chromosome (from a X/Y interchange at paternal meiosis), or on an autosome (from a Y/autosome translocation in the father), in particular SRY (Sex determining Region, Y chromosome). Other sex determining genes, usually sitting on gonosomes or on autosomes are likely to be involved.
H - XY FEMALE SYNDROME
- Epidemiology: 0.1 / 1 000 female births.
- The phenotype is that of a female with ovarian failure, and with or without other stigmata (e.g. sexual anomalies, limbs anomalies).
- Sex reversal in XY females can be due to mutations in SRY in 15%, or to other known or unknown genes mutations; some of these genes map to autosomes (e.g. SOX9 on chromosome 17).
I - NOONAN SYNDROME
- formerly called Turner syndrome with a normal karyotype (46, XX or 46, XY) from the shortness and other common signs: this is why it is herein cited. It is in fact an autosomal dominant trait.
- cardiac malformations, mild mental retardation, infertility or fertility.
- a gene maps in 12q24.
OTHER CHROMOSOME IMBALANCES
A - TRIPLOIDY
- Epidemiology: the most frequent chromosome aberration in early miscarriages; found in 20 % of spontaneous miscarriages. Stillbirths are also frequent; livebirth can occur, but the baby dies shortly afterwards.
- Karyotype: 3N = 69 chromosomes: i.e. 69, XXX, or 69, XXY, or rarely 69, XYY; due to a fertilisation anomaly: digyny: non-expulsion of the 2nd polar body; or diandry: fertilisation of 1 oocyte I by 2 spermatozoa. Diandry is 4 times more frequent than digyny.
- Clinics: Preeclampsia; large placenta, with frequent hydatiform mole; severe growth retardation; microcephaly; syndactily; heavy brain, heart, kidney and ocular malformations leading to death.
B - TETRAPLOIDY
4N = 92 chromosomes. Found in 5 % of miscarriages. Literature records very few live births, but with death soon after.