Edition 59 - 2016, July / Images

Images in Pediatric Endocrinology: NEONATAL CUSHING’S SYNDROME – Ed. 59

Cintia Morales, Mara Feresín, Silvia Gil, y Mariana Costanzo

Servicio de Endocrinología. Hospital de Pediatría Juan. P Garrahan, Buenos Aires, Argentina

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A and B cushingoid phenotype, hirsutism, synophrys, acne, prominent abdomen, normal male genitalia with bilateral hydrocele.

Clinical case:

The patient was admitted at the Endocrinology department because of increased levels of 17OHP4 in the newborn screening. The baby was born at term, adequate weight for gestational age (Gestational age: 40 week, weight: 3.690 kg, length: 48.5 cm and head circumference: 35 cm), normal vaginal delivery, without relevant perinatal antecedents. Two samples of neonatal screening were requested, the first one 24 hs after birth was reported to be normal, but the second one, at 21 days of life showed a level of 17OHP4 of 33.6 ng/ml (VN < 25.4 ng/ml).

First evaluation in our institution was performed at 2.5 months of age. Anthropometric data: weight: 4.560 kg (-1.94 SDS), length: 52.5 cm (-3.53 SDS) and head circumference: 35.5 cm (< 2 SDS). Physical exam showed pallor, cushingoid phenotype, hirsutism, synophrys, acne, prominent abdomen without visceromegalies, normal blood pressure (BP 71/45 mmHg, PC 50), normal male genitalia, bilateral scrotal testes (1-2 cc volume) with bilateral hydrocele.

Considering the clinical appearance, linear growth arrest and microcephaly, hypercortisolism was suspected and the following studies were requested:

Biochemical determinations:
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  • Abdominal ultrasound: bilateral enlargement of the adrenal glands with preserved structure. Venous-venous shunt (left portal vein and left hepatic vein).

Hepatic transaminases and gamma-glutamyl transpeptidase were increased, probably related to the shunt, as it was proposed by the Hepatologists.

With the diagnosis of ACTH independent Cushing´s Syndrome and ultrasound compatible with bilateral adrenal hyperplasia, adrenalectomy was indicated. To improve symptoms of hypercortisolism the patient started on ketoconazole together with ursodesoxicolic acid until surgery could be performed. Liver function tests remained stable. Laparoscopic bilateral suprarrenalectomy was successful. After surgery the patient presented with adrenal insufficiency and started hydrocortisone and fludrocortisone replacement therapy. Histological analysis revealed bilateral cortical nodular adrenal hyperplasia.

Final diagnosis was ACTH-independent Cushing’s Syndrome secondary to Bilateral Adrenal Hyperplasia. Hyperpigmented skin spots, bone lesions or other endocrine disorders associated with McCune Albright syndrome were not present. Echocardiogram showed mild left ventricular hypertrophy with preserved heart function.

Molecular analysis of protein G alpha subunit gene in the adrenal tissue is still in process.

Comment

Cushing’s syndrome (CS) results from the presence of high and sustained circulating concentrations of glucocorticoids (GC). CS can be secondary to a primary increased in cortisol production in the adrenal cortex (endogenous CS) or, most frequently, to the administration of GC for the treatment of several chronic diseases (exogenous CS). Endogenous CS is a rare and life threatening disorder that should be assessed by a multidisciplinary team with experience in the field.

The etiology of CS can be grouped in two main categories: ACTH-dependent and ACTH-independent CS (Table 1).

Table 1

ACTH-dependent Cushing´s syndrome

  • ACTH producing pituitary adenoma (Cushing´s Disease)
  • Ectopic production of ACTH
  • Ectopic production of CRH

ACTH-independent Cushing´s syndrome

  • Corticoadrenal Tumors (adenoma/carcinoma)
  • Nodular Adrenal Hyperplasia

Bilateral adrenal hyperplasia is a group of disorders associated with ACTH independent CS. These conditions include primary pigmented adrenocortical disease (PPNAD), ACTH independent macronodular adrenal hyperplasia (AIMAH) and nodular adrenocortical hyperplasia associated with McCune Albright syndrome (MAS).

PPNAD is characterized by adrenal atrophy and multiple small nodules containing a lipochromic pigment resulting in a characteristic yellow color and internodular adrenal atrophy. In 95% of cases it is a component of Carney´s complex which includes lentigines, cardiac myxomas, and endocrine and non endocrine tumors. Inactivating mutations of the 1α regulatory subunit of protein kinase A have been reported in patients with PPNAD, isolated or associated to Carney´s Complex.

AIMAH is a very infrequent condition of unknown etiology that leads to overt CS. Both adrenal gland are enlarged (up to 10-100 fold) and show non-pigmented nodules.

MAS has the following clinical triad: polyostotic fibroid dysplasia, café-au-lait spots in the skin and peripheral precocious puberty in girls (along with other clinical disorders, such as CS secondary to ACTH-independent nodular adrenal hyperplasia, hyperthyroidism, hyperprolactinemia and GH excess). MAS is the most frequent cause of CS in the infant. Evolution of CS can be fairly aggressive in these patients requiring bilateral adrenalectomy.

The following signs and symptoms were reported in patients with CS associated to MAS: low birth weight for gestational age (50%), round facies (67%), failure to thrive (60%), hypertension (33%), nephrocalcinosis (30%), hirsutism (27%), hyperglycemia (20%), and linear growth arrest (10%). Microcephaly, cholestasis, and hyperandrogenism were found in neonatal cases. However to our knowledge there are no reports on abnormal neonatal screening in these patients. Long term sequelae of Cushing’s syndrome in MAS include a significantly increased prevalence of cognitive disorders, including specific learning or speech disorders, or global developmental delay and speech apraxia.

In all published cases of MAS, a post zygotic mutation in protein G alpha regulatory subunit has been found, the alpha substitution of Arg201 giving rise to a constitutively active protein.

Bilateral adrenalectomy is indicated in cases of adrenal hyperplasia secondary to PPNAD, AIMAH, y MAS. After surgery, replacement therapy with gluco and mineralocorticoids is necessary. Spontaneous remission of CS has been reported in MAS, but it is impossible to predict in which patients this will occur.

References

  1. Costanzo M, Guercio G, Ciaccio M, Rivarola MA, Belgorosky A. Evaluación de eje suprarrenal- Síndrome de Cushing. www.endopedonline.com.ar, 24th issue, July 24, 2009
  2. Storr HL, Chan LF, Grossman AB, Savage MO. Paediatric Cushing syndrome: epidemiology, investigation and therapeutic advances. Trends Endocrinol Metab 2007; 18: 167-174
  3. Collins MT et al. McCune-Albright syndrome and the extraskeletal manifestations of fibrous dysplasia Orphanet Journal of Rare Diseases 2012, 7(Suppl 1):S4
  4. Paris F, Philibert P, Lumbroso S, Servant N, Kalfa N, Sultan C. Isolated Cushing’s syndrome: an unusual presentation of McCune-Albright syndrome in the neonatal period. Horm Res. 2009;72(5):315-9.

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