Edition 58 - 2016, May / Images

Images in Pediatric Endocrinology: CRANIAL OSTEOESCLEROSIS IN A PATIENT WITH PSEUDOHYPOPARA-THYROIDISM TYPE 1B – Ed. 58

Mara Feresin MD1, Valeria De Dona MD1, Mariana Costanzo MD1, Gisela Viterbo MD1.

Servicio de Endocrinología1 y Servicio de imágenes2. Hospital de Pediatría “Prof. Dr. J. P. Garrahan”, Combate de los Pozos 1881, Buenos Aires, Argentina.

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Figure 1: Calvarium thickening (arrow head), periodontal lamina dura (dashed-line arrow) “salt-and-pepper” appearance, and multiple well-defined calcium-density round lesions (full-line arrow). It was not possible to define if they were from intra- or extracranial origin.

CASE REPORT:

A 14 year-old male adolescent was referred to our hospital with the diagnosis of progressive bilateral genu valgum. He was born at term (39 weeks), with normal birth weight (3450 g), without remarkable perinatal or family history. At 8 years of age, he complained of bone pain in the knees and hips. A diagnosis of bilateral slipped capital femoral epiphysis. Corrective surgery was performed at 10 years old. He was unable to walk for 7 months after surgery. At the age of 13 years, he presented with bilateral genu valgum. After undergoing through bilateral hemiepiphysiodesis he was referred to our hospital.

Physical exam:

The patient was eutrophic. His weight was: 49 Kg (SDS -0.18), height: 161.8 cm (SDS 0.39), BMI 18.7 (SDS 0.20), HC: 56 cm (SDS 1.00). Bilateral genu valgum was more evident on the left side, with an intermalleolar distance of 23 cm (Normal value: 2.3 cm, SD 2.48 cm) [i]. Pubertal Tanner stage was Genital 4, Pubic Hair 4, testes 12/15ml.

To rule out a calcium metabolism disorder, further studies were requested:

-Laboratory test showed hypocalcemia, hyperphosphatemia with elevated parathyroid hormone (PTH) (table 1).

-Radiographs (figure 2) showed osteomalacia in every metaphysis and fibrous osteitis at the phalanges. On the lateral skull radiograph, calvarium thickening, absent lamina dura and multiple well-defined calcic-density round lesions were found.

-Computed tomography (CT) of the brain showed that those images were located at the calvarium diploe, and the intracranial origin was ruled out (figure 3).

As the diagnosis of Pseudohypoparathyroidism type 1b was suspected, the patient was started on calcitriol and calcium carbonate, with good response.

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Figure 2: A.– Surgical instrumentation at the femoral head, distal femurs, and proximal tibias. Genu valgum. B.– Left ankle with osteomalacia. C.– Humeral  metaphysis with osteomalacia. D and E.– Osteopenia, bone age of 16 years. Fibrous osteitis at the 5th phalanx.

Table 1: Biochemical studies

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Figure 3: Brain CT shows sclerotic images in the calvarium diploe.

DISCUSSION

Serum calcium and phosphorus homeostasis is regulated basically by PTH and Vitamin D. PTH actions are mediated by a G protein-coupled receptor (Gsα), encoded by GNAS, a 13 exons gene in chromosome 20 q.13.  In kidney, PTH stimulates calcium reabsorption at the distal tubule. At the proximal tubule, PTH stimulates the synthesis of 1,25(OH)2D (calcitriol), the active form of vitamin D, and inhibits phosphate reabsorption.  . Both, PTH and calcitriol, stimulate bone resortion. Calcitriol also stimulates intestinal  calcium and phosphate absorption.

Pseudohypoparathyroidism (PHP) is an heterogeneous group of hereditary disorders characterized by hypocalcemia and hyperphosphatemia due to inability of parathyroid hormone (PTH) to elicit appropriate biological responses in its target tissues. PTH resistance occurs in the proximal renal tubule, whereas no resistance appears to exist neither in the distal renal tubule or the bone. Consequently, calcitriol synthesis and phosphate excretion are diminished. Therefore, hypocalcemia, hyperphosphatemia and elevated PTH concentrations are found in these patients.

Clinical manifestations are the result of hypocalcemia, however, patients with chronic hypocalcemia may remain asymptomatic. Chvostek and Trousseau signs are usually present. Posterior subcapsular cataracts, calcification of intracranial structures and spondyloarthopathy may be observed as well. Cranial osteosclerosis is extremely rare.

PHP is caused by mutations and/or deletions in the GNAS gene complex. Genomic imprinting plays an important role in the regulation of its expression. Gsα expression is predominantly maternal in a small number of tissues, where the transcription from the paternal allele is silenced (i.e. proximal renal tubules, thyroid gland and pituitary). Only maternal transmission of the genetic defect lead to PHP 1a, 1b and 1c (with hormone resistance) while paternal transmission is associated with pseudopseudohypoparathyroidism (PPHP, without hormone resistance).

Patients with maternal inherited heterozigous mutations in exons 1-13 of the GNAS gene present with PHP 1a phenotype, while PHP 1b phenotype is due to methylation defects or mutations that affect GNAS complex imprinting.

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BIBLIOGRAPHY:

-Mishaela R. rubin and Michael A Levin. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Eighth Edition. 2013. Chapter 72 and 73.

-G. Perez de Nanclares y col. Pseudohipoparatiroidismo: Diagnóstico genético. An Pediatr (Barc). 2009;70 (Espec Cong 1): 6-14.


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