Page 211 - Concise Pathology for Exam Preparation ( PDFDrive )

196 SECTION I General Pathology

Q. Describe disorders involving sex differentiation in both males
and females.
Ans. An XY karyotype leads to differentiation of the primitive gonadal tissue into
sex cords (seminiferous tubules) and Leydig cells, whereas an XX karyotype leads to
preferential development of the germinal cortex into primordial follicles.
• A true hermaphrodite has both male and female gonads (ovary and testis).
• A pseudohermaphrodite is a person whose phenotype (appearance) is not in agreement
with the genotype (true gonadal sex).
• A male pseudohermaphrodite is a genotypic male (XY with testes), who phenotypically
resembles a female (eg, testicular feminization).
• A female pseudohermaphrodite is a genotypic female (XX with ovaries), who
phenotypically resembles a male (eg, virilization in congenital adrenal hyperplasia).
• Testicular feminization is due to deficiency of androgen receptors (testosterone is
unable to cause development of the seminal vesicles, epididymis) and vas deferens.

Q. Write briefly on Mendelian inheritance disorders.
Ans. Single gene defects (mutations) follow the Mendelian pattern of inheritance and are
called Mendelian disorders. Mutations involving single genes usually follow one of the
following three patterns of inheritance:
1. Autosomal dominant (AD) disorders
(a) Only one abnormal allele is necessary to express the disease (manifests in the het-
erozygous state).
(b) AD diseases are characterized by reduced penetrance, variable expressivity, and in
some cases, late onset of the disease (eg, familial polyposis, Huntington chorea).
Each affected individual has an affected parent unless the condition has arisen from
a new mutation in the germ cells forming that individual.
(c) Phenotypic expression of an inherited mutant gene or percentage carriers of the
gene who express the trait is called penetrance. When some individuals inherit the
mutant gene but are phenotypically normal (ie, a patient may have the abnormal
gene but never expresses the disease), the trait is said to exhibit reduced
penetrance.
(d) If a trait is seen in all individuals carrying the mutant gene but they express the
disease with different severity, it is called variable expressivity (eg, neurofi-
bromatosis).
(e) The manifestations of these disorders depend on the nature of protein affected and
the type of mutation. ‘Loss of function mutations’ may affect proteins involved in
control of complex metabolic pathways dependent on feedback regulation,
eg, mutation in gene responsible for synthesis of low density lipoprotein (LDL)
receptor results in decrease in the number of the same leading to increased choles-
terol levels; or structural proteins like collagen, a reduction of which leads to skel-
etal abnormalities. ‘Gain of function mutations’ are less common and may lead to
enhanced normal function of the protein, eg, increased activity of enzymes; or may
induce a new function in addition to the normal function of the protein, eg, hun-
tingtin in Huntington disease, which is neurotoxic to neurons.
Examples: von Willebrand disease, familial hypercholesterolaemia, adult polycystic
kidney, Huntington chorea, congenital spherocytosis, familial polyposis, neurofibro-
matosis and Marfan syndrome.
Neurofibromatosis is associated with neurofibromas, iris hamartomas (Lisch
nodules), café-au-lait spots, skeletal lesions (scoliosis) and an increased incidence
of other tumours (acoustic neuromas, meningiomas, optic nerve gliomas and
pheochromocytomas).
Marfan syndrome, due to a defect in fibrillin, primarily affects the skeleton (eunuchoid
habitus and arachnodactyly), eyes (dislocated lens) and cardiovascular system (mitral
valve prolapse and dissecting aortic aneurysm).

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