The Principles of Clinical Cytogenetics - Extra Materials - Springer

Sex Chromosomes and Sex Chromosome Abnormalities 225
amenorrhea or mild developmental delay (169,173–175), many have had a more severe phenotype
with mental retardation and birth defects (173).
In males with unbalanced X;autosome translocations, there is in utero lethality or, if they survive,
multiple congenital anomalies and mental retardation (176).
Deletions of Xp
Males with deletions of the short arm of the X show contiguous gene syndromes characterized by
different combinations of phenotypes, depending on the location and length of the deletion (177).
X-linked ichthyosis, Kallmann syndrome (anosmia and hypogonadism), mental retardation, and chondrodysplasia
punctata (skeletal dysplasia) are seen in males with deletions involving distal Xp. Deletions
in Xp21 could cause a contiguous gene syndrome of Duchenne muscular dystrophy, retinitis
pigmentosa, adrenal hypoplasia, mental retardation, and glycerol kinase deficiency (178). Larger Xp
deletions in males are lethal.
In females, there is usually preferential inactivation of the structurally abnormal X when the deletion
is in or proximal to Xp22.1. In those with breakpoints in Xp22.3, the normal and abnormal X can
be active in various proportions of cells (179). Females with Xp deletions do not usually manifest any
of the recessive disorders because of the presence of a normal X chromosome, although almost all
have short stature and some have Turner syndrome phenotypic features. Short stature in these patients
is likely the result of haploinsufficiency for the SHOX gene, within the pseudoautosomal region on
Xp (41,180). Turner syndrome features could include variable skeletal anomalies associated with
SHOX deletion and soft tissue anomalies such as nuchal webbing and low posterior hairline reported
in some patients with Xp11.1 terminal deletions possibly related to a proposed lymphedema critical
region in Xp11.4 (43,44).
Females with terminal deletions at Xp11.1 usually have complete ovarian failure, although in a
series reported by Ogata et al., almost 50% of those with deletions in this region had spontaneous
puberty and one had fertility (181). Females with terminal deletions originating at Xp21 are more
likely to show premature rather than complete ovarian failure (182), although they may have normal
fertility (181). The phenotypes associated with Xp deletions can vary, even within the same family
(183). This is most likely the result of variable X inactivation and modifying genes.
Studies have shown that most de novo Xp deletions originate on the paternal chromosome (179).
UPD (see Chapter 19) for the deleted and nondeleted X chromosomes was not found in a study of 25
females with Xp deletions (179).
Deletions of Xq
Large Xq deletions in males are not compatible with survival. Smaller deletions are associated
with severe phenotypes (184).
Deletions of the long arm of the X lead to variable phenotypic outcomes in females. Forty-three
percent of women with Xq deletions have short stature (185). In a study by Geerkens et al., it was
found that women with breakpoints in Xq13 to Xq25 had both average and short stature, suggesting
a variable inactivation of growth genes in Xp or proximal Xq (186). Deletions in various regions of
the long arm are sometimes associated with gonadal dysgenesis or POF. Females with terminal deletions
originating at Xq13 are more likely to have complete ovarian failure, whereas those with deletions
at Xq24 might have POF (182). In a series of women with Xq deletions ranging from Xq13.3 to
Xq27 reported by Maraschio et al., seven of eight patients had secondary amenorrhea (187). One
woman with deletion at Xq27 had fertility and menopause at 43 years. Clinical features of Turner
syndrome are less common in Xq as compared to Xp deletions (188), but more common in patients
with deletions proximal to Xq25 (187). The likelihood of an abnormal phenotype in a female with an
Xq deletion is low, although primary or secondary ovarian failure is likely. Women with Xq deletions
and fertility should be advised about their 50% risk of passing the abnormal X to male offspring, with
likely miscarriage or severe phenotype, depending on the size of the deletion.