Case Report
Two Neonatal 21-Hydroxylase Deficiency Cases without Hyperpigmentation
Ahmet Ozdemir1*, Selim Kurtoglu1,2, Ulku Gul2, Nihal Hatipoglu2 and Tamer Gunes1
1Department of Pediatrics, Division of Neonatology, Erciyes University, Turkey
2Department of Pediatrics, Division of Pediatric Endocrinology, Erciyes University, Turkey
*Corresponding author: Ahmet Ozdemir, Department of Pediatrics, Division of Neonatology, Erciyes University School of Medicine, Talas Street, 38039, Kayseri, Turkey
Published: 11 Sep, 2018
Cite this article as: Ozdemir A, Kurtoglu S, Gul U,
Hatipoglu N, Gunes T. Two Neonatal
21-Hydroxylase Deficiency Cases
without Hyperpigmentation. Ann Clin
Case Rep. 2018; 3: 1544.
Abstract
The majority of cases of salt-losing congenital adrenal hyperplasia present with 21-hydroxylase
deficiency in the newborn period. In females it is recognized by the uncertainty of the external
genitalia and in males by macro genitalia. The presence of hyperpigmentation is an important finding
of adrenocorticotropic hormone along with melanocyte stimulating hormone, especially on the
nipples and genitals in babies. However, some patients may not have hyperpigmentation. This paper
emphasizes that patients with 21-hydroxylase deficiency may not always have hyperpigmentation
and that surrenal ultrasonography is important in the diagnostic studies.
Keywords: Newborn; White Addison; 21-Hydoxylase deficiency
Introduction
Congenital Adrenal Hyperplasia (CAH) is a disease series which presents with enlargement of the adrenal glands with ACTH increase due to the deficiency of enzymes playing a role in cortisol synthesis [1,2]. The diseases include StAR, 3-beta–hydroxysteroid dehydrogenase deficiency (3β-OHSD), 21-hydroxylase and 11-hydroxylase deficiency, respectively in order, but the most common form is 21-hydroxylase deficiency. It is divided into two groups as classic or non-classic type [1-3]. Classic forms are examined under two groups, the type causing salt wasting and the common virilizing type. Most of the forms causing salt wasting in newborns are 21-hydroxylase deficiency cases. In female newborns, it can be observed as cases with a masculine external appearance with clitoromegaly, ambiguous genitalia or bilateral cryptorchidism or it may cause findings such as macrogenitalia in boys, pigmentation in the nipples-genital area or general hyperpigmentation in both genders [1-3]. However, pigmentation may not develop in every case. These cases are called "non-pigmented CAH" or "white Addison" [4,5]. The clinical significance of the topic was emphasized in this paper by presenting two cases who are hospitalized with salt wasting crisis presentation in which pigmentation was not observed.
Case Presentation
Case 1
It was learned that the 23 day old baby referred to our hospital with complaints of discomfort
and inability to gain weight had been born full-term with a birth weight of 3260 gr but had been
unable to gain weight since about 10 days of age and she was restless. In the physical examination,
her weight was measured as 3220 gr, height as 51 cm, head circumference as 35.5 cm and blood
pressure as 93/56 mmHg. Her external genital structure had a masculine appearance, phallus was 2.3
cm, bilateral scrotal structure was empty and gonads were un-palpable. There was no pigmentation
in the nipple and genital area in the patient. Suitable water-electrolyte treatment was started after
diagnosis of dehydration and surrenal deficiency with laboratory findings. In the abdominal
ultrasonography made on the day she was hospitalized, the uterus and ovary structures were found
and surrenal glands were bigger than normal size and in cerebriform structure. With karyotype
and hormonal results, virilized female and salt depleting 21-hydroxylase deficiency were diagnosed
(Table 1). Treatment with hydrocortisone, mineralocorticoid and salt replacement was started. In
the peripherical blood sample of the patient which was evaluated for genetic diagnosis, deletion
was detected in the CYP21A2 gene of the patient in line with 21-hydroxylase and salt wasting type.
Case 2
It was learned that the male baby brought to the hospital with diarrhea and vomiting complaints on his postnatal 20th day had been born full-term with a birth
weight of 3800 gr. Diarrhea-vomiting complaints had started on
approximately the 13th day after birth and he was unable gain weight.
His height was 53 cm, weight was 3650 gr, head circumference was
38 cm and average blood pressure was 55 mmHg in his physical
examination. In the genital examination of the infant, who had a
low fontanel and dry mouth, it was observed that the testicles were
in the scrotum and the penis length was 4.5 cm (normal: 2.5 cm to
4.5 cm). There was no pigmentation in the nipple and genital area
of the patient. Dehydration and surrenal deficiency were considered
since thrombocytosis was also present in the patient in addition to
hyponatremia and hyperpotassemia. In surrenal ultrasonography, it
was observed that the surrenal glands were bigger than normal. The
hormonal findings of the infant, who was started on dehydration and
surrenal crisis treatment, were in line with salt wasting 21-hydroxylase
deficiency (Table 1). Hydrocortisone, mineralocorticoid and salt
replacement treatment was started and in the peripherical blood
sample of the patient evaluated for genetic diagnosis, deletion
was detected in the CYP21A2 gene of the patient in line with
21-hydroxylase and salt wasting type.
Table 1
Discussion
Salt wasting 21-hydroxylase deficiency accounts for most of
the surrenal crisis cases seen in the newborn period [1-3]. Clinical
presentation of the cases is related to cortisol and mineralocorticoid
deficiency. Also virilization in females and macrogenital structure in
males occur due to increased androgen levels [1]. Another significant
and stimulating physical examination finding in the diagnosis of
the patients is hyperpigmentation which is more significant in the
nipples, axillary and genital area [1]. Hyperpigmentation is related
to increased melanocyte-stimulating hormone (MSH) level with
increased ACTH. Serum and urine electrolytes, plasma renin activity,
aldosterone, cortisol, 17-OHP, Dehydroepiandrosterone Sulfate
(DHEA-S), androstenedione and total testosterone levels are studied
in patients after physical examination. The definite diagnosis is made
with the presence of mutations with genetic study. The presence of
thrombocytosis in addition to hyponatremia and hyperpotasemia in
cases with hyperpigmentation supports surrenal crisis [6,7]. Indeed,
thrombocytosis was observed in both infants.
It is important to examine the surrenal gland and inner
genital organs with ultrasonography in these cases. While surrenal
ultrasonography adrenal gland dimensions in normal newborns are
nearly 14.4 mm in length and 1.9 mm in width, these measurements
are above 20 mm and 4 mm, respectively, if surrenal hyperplasia is
present [8]. Another important finding is a cerebriform appearance
in the surrenal glands [9]. The surrenal glands were large in both of
our cases and cerebriform appearance was present in one of them.
It should not be forgotten that renal pathologies may also cause
pseudohypoaldosteronism in cases presenting with salt wasting
crisis and renal ultrasonographic evaluation should also be done in
addition to surrenal evaluation [10].
ACTH and melanocortin level increases in congenital adrenal
hyperplasia cause pigmentation on the skin. Melanocytes are the
population of intraepidermal dendritic cells occurring on the 50th
day of intrauterine life and they produce melanin pigment [11].
Connecting to the ACTH and melanocortin melanocyte receptors,
they cause an abnormal increase in melanin production. However,
in some of the primary adrenal deficiency cases, it was observed
that pigmentation did not form and the cases were named "white
Addison" [12,13]. Some patients with a disorder affecting the
hypothalamus and hypophysis may be pale as ACTH and MSH levels
decrease [13]. However, although ACTH and MSH levels are high, a
pigmentation loss due to a high degree of melanosome decomposition
occurs in melanin-producing cells [4,5]. The reason for melanosome
decomposition is not clearly known. Pigmentation loss in addition to
very high ACTH was also observed in our cases.
Similarly, no pigmentation increase was observed in a case with familial glucocorticoid deficiency demonstrating high ACTH-related
hyperpigmentation. When the reason was examined, it was reported
that pigmentation did not occur because there was a mutation in
the ACTH receptor genes the melanocortin 1 receptor (MC1R) and
melanocortin 2 receptor (MC2R) [14].
As a result, the presence of pigmentation in CAH diagnosis,
which is the main reason for neonatal surrenal crisis that is lifethreatening
and which should be treated with early diagnosis, is an
important finding. However pigmentation increase may not always
take place, as in our case.
Conclusion
Even though there is no pigmentation increase in newborn cases with presentation of dehydration, hyponatremia, hyperpotassemia and thrombocytosis, we would like to emphasize the need to conduct urgent surrenal and renal ultrasonography in addition to hormonal evaluations for CAH diagnosis.
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