2137.2 Stepwise Analysis
The index case presented at the age of 19 years with delayed pubertal development.
Delayed puberty in boys is defined as lack of pubertal development by the age of
14 years which is in correspondence with 2.5 SD above the mean for the popula-
tion. The main differentials for the delayed pubertal development between the age
of 14–18 years are constitutional delay in growth and puberty (CDGP) and hypo-
gonadism. However, the adolescents with CDGP enter into puberty by the age of
18 years; hence, the possibility of CDGP after this age is virtually excluded. Our
patient presented at the age of 19 years with poor development of secondary sexual
characteristics; therefore, the diagnosis of hypogonadism as a cause of delayed
puberty was considered. Development of secondary sexual characteristics results
from both adrenarche and gonadarche which may overlap or come in succession.
Though the first sign of puberty in boys is testicular enlargement (TV ≥ 4 ml), only
in 1 % of boys’ pubarche precede the gonadarche. On the contrary, in 20 % of girls,
pubarche precedes the thelarche. Patients with hypogonadism usually have normal
onset of adrenarche, but pubarche is delayed as was seen in our patient who had
appearance of pubic hair at the age of 15 years without evidence of gonadarche.
This is because the weaker adrenal androgens require conversion to potent andro-
gens in functional testes for induction of pubarche. The presence of anosmia, mid-
line defects, synkinesia, eunuchoidal proportions, small soft testes, skeletal
anomalies, and neurological deficits (nystagmus and ataxia) usually suggests the
diagnosis of IHH. Further, the manifestations of IHH vary according to the age of
presentation; infants present with micropenis and cryptorchidism, adolescents with
delayed or arrested puberty and gynecomastia, and adults with infertility. Long-
leggedness, gynecomastia, small firm testes, learning disabilities/behavioral abnor-
malities, and some degree of virilization favor the diagnosis of Klinefelter’s
syndrome which is considered as prototype of hypergonadotropic hypogonadism.
Our patient had eunuchoidal proportions, skeletal deformities (genu valgum), and
small soft testes which support the diagnosis of hypogonadotropic hypogonadism.
Low LH and low testosterone below the reference range confirm the diagnosis of
hypogonadotropic hypogonadism. LH response to short-acting GnRH agonist
(triptorelin) and testosterone response to hCG were prepubertal in our patient, fur-
ther substantiate the diagnosis of hypogonadotropic hypogonadism. However,
these dynamic tests help in differentiating between CDGP and IHH and are not
required if the patient is above the age of 18 years. High LH, FSH, and low testos-
terone indicate hypergonadotropic hypogonadism and require further evaluation
by karyotyping to establish the diagnosis of Klinefelter’s syndrome.
Hypogonadotropic hypogonadism can be due to hypothalamic or pituitary lesion
or due to familial or sporadic genetic mutations. The index patient was diagnosed
to have isolated hypogonadotropic hypogonadism, as other pituitary hormone pro-
file was normal and MR brain imaging was unremarkable. Patients of IHH with
anosmia or hyposmia are termed as Kallmann syndrome. Defective migration of
olfactory neurons from olfactory placode to bulb results in impaired development
of olfactory bulb and consequent anosmia. This is evident in MRI as olfactory bulb
aplasia/hypoplasia and absent olfactory sulci. Since our patient did not have hypos-
mia/anosmia, he was considered to have normosmic variant of IHH. The aims of
7 Delayed Puberty