Sclerochoroidal calcification associated with Albright's hereditary osteodystrophy

Abstract

A 47-year-old woman presented with bilateral gradual loss of vision, ocular discomfort and seeing a black shadow in her right visual field over 6 months duration. Her medical history was extensive including: developmental delay, pseudohypoparathyroidism, hypertension, spinal stenosis, epilepsy and suspected idiopathic intracranial hypertension. Ocular examination revealed choroidal elevation in both eyes, which were highly ecogenic on ecography and confirmed to be calcifications of choroids on CT scan in her both eyes. She had subnormal vision and reduced colour vision in her both eyes. Electrodiagostic studies suggested rod dysfunction. She had typical features of Albright's hereditary dystrophy and was positive for the GNAS 1 mutation. She is currently being monitored by ophthalmologlists and is also under a medical team undergoing further assessment with regard to her treatment.

Background

We report the first documented case in the UK of sclerochoroidal calcification associated with pseudohypoparathyroidism (PHP) type 1a. We describe the electroretinogram (ERG) findings associated with this condition and postulate as to the involvement of the G proteins involved in normal photoreceptor functioning.

Case presentation

RPW is a 47-year-old right-handed female nurse, who presented to the ophthalmology clinic with gradual deterioration in her vision in both eyes, right greater than left. This was associated with pain at the back of both eyes and photophobia. She described a persistent black shadow in her right visual field.

Her current medications include: calcitriol 1 µg once daily, bendroflumethiazide 10/95 2.5 mg once daily, tramadol 100 mg four times a day, levothyroxine 200 µg once daily, magnesium oxide, 320 mg three times a day, domperidone 10 mg three times a day/PRN, Qvar 100 inhaler two puffs twice daily, lamotrigine 75 mg twice daily and fexofenadine 120 mg once daily.

Her medical history is extensive, and of note included developmental delay and hypocalcaemia which was identified in 1974 at the age of 11. Unfortunately, there were no records available of her metabolic parameters prior to her receiving treatment but were reported in the clinical letters from that time to show hypocalcaemia with a parathyroid hormone (PTH) within normal limits. She was diagnosed with PHP and was placed on vitamin D, the dose of which was titrated up based on regular blood tests of her calcium and phosphate levels. There was evidence of subcutaneous calcinosis later identified at the age of 12 years.

She also has been treated for hypertension, tension headaches and epilepsy. She was investigated with regard to her headaches in Hong Kong in 1981 and was diagnosed with idiopathic intracranial hypertension. Repeat lumbar punctures were subsequently carried out in the UK, which did not confirm this diagnosis. She has more recently had a diagnosis of spinal stenosis. The typical features of Albright's hereditary osteodystrophy (AHO), including short stature, round face, obesity, brachydactyly and subcutaneous calcifications, were present. She was positive for the GNAS 1 gene mutation.

On examination, her visual acuities on presentation were 6/12 in each eye. There was no significant refractive error. Her intraocular pressures were within normal limits. Her colour vision on Ishihara testing was 10/17 in the right eye and 14/17 in the left eye. Dilated examination revealed the presence of bilateral choroidal elevation superiorly, right more than left. These lesions were highly echogenic on B scan ultrasound, indicating possible calcification. CT scanning of both orbits confirmed the presence of bilateral choroidal calcification. An ERG was performed that suggested mainly rod dysfunction. Although initially it was felt that this might be sarcoidosis, measurements of her metabolic parameters ruled this out (table 1).

Table 1.

Metabolic parameters

Parameter	Value	Normal range
Albumin	43 g/l	35–50
Calcium	2.32 mmol/l	2.2–2.6
Inorganic phosphate	1.47 mmol/l	0.8–1.5
Alkaline phosphatase	106 IU/l	30–130
Alanine transaminase	35 IU/l	2–53
Total bilirubin	14 µmol/l	0–21
ACE	16 IU/l	8–52

A diagnosis of sclerochoroidal calcification secondary to Albright's hereditary osteodystrophy was made (figure 1).

Figure 1.

(A) Axial section from CT scan demonstrating extensive calcification of the choroids right and left eye (arrows). (B) and (C) Fundus photos of right and left eye, respectively, demonstrating bilateral elevated subretinal lesions superiorly. (D) B scan ultrasound showing highly echogenic reflection (arrow) indicating possible calcification.

Discussion

Sclerochoroidal calcification is characterised by typical geographic yellow white fundus lesions that usually occur bilaterally in adults.¹ It is a condition usually seen in older (median age, 70 years) asymptomatic patients and the typical location is the post equatorial and superotemporal retina.² Sight threatening complications that have been reported with sclerochoroidal calcification include choroidal neovascularisation and^3–5 serous detachments.⁵

Its differential diagnosis includes a number of intraocular tumours such as choroidal metastasis, choroidal melanoma , lymphoma, choroiditis and choroidal osteoma. Calcification can be dystrophic or metastatic. The causes of sclerochoroidal calcification can be divided into four groups:

1. idiopathic,

2. hypercalcaemic conditions: hyperparathyroidism, PHP, hypervitaminosis D, vitamin D intoxication and sarcoidosis,

3. metabolic: Gitelman syndrome and Bartter syndrome,

4. hereditary: familial articular chondrocalcinosis.

Sclerochoroidal calcification is most often idiopathic, where calcium phosphorous metabolism is normal. This is a dystrophic condition and the calcification is believed to be deposited at the sites of insertions of the oblique extraocular muscles.⁶ It is speculated that this is related to longstanding chronic tension of the muscle. It requires no treatment, but screening should be carried out to exclude an underlying systemic disorder.

Gitelman syndrome and Bartter syndrome are autosomal-recessive conditions of hypokalaemic alkalosis associated with hypomagnesemia and deposition of calcium salts in various tissues.¹ There is a defect in the thiazide-sensitive Na–Cl cotransporter in the distal convoluted tubule.⁷ Differentiation of these two conditions is achieved by measuring urinary calcium. In Gitelman syndrome hypocalciuria is noted, whereas in Bartter syndrome normal or high urine calcium is seen. It has been postulated that the sclerochoroidal lesions in Gitelman syndrome are deposits of calcium pyrophosphate dihydrate crystals (CPPD disease).² Magnesium is a cofactor for alkaline phosphatase, and thus hypomagnesaemia may reduce the activity in this enzyme and result in an increase in extracellular inorganic pyrophosphate, and predisposes to CPPD. Diagnosis of these conditions is important as they are potentially treatable.

There has been a familial case of sclerochoroidal calcification described.⁸ This occurred in association with chondrocalcinosis, which was inherited in an autosomal-dominant manner. This condition is associated with CPPD. There was a 24-year follow-up of the proband, who had presented with reduction in vision and this demonstrated progressive involvement of the macula.

PHP refers to several distinct, but related disorders in which resistance towards PTH is the most prominent feature. This includes PHP1a–c, PPHP and PHP2. These conditions can be differentiated by the presence (PHP1a and c) or absence (PHP1b) of resistance to hormones other than PTH that act via Gs-coupled receptors such as thyroid-stimulating hormone, glucagons and gonadotrophins and the presence or absence of GNAS1 defect (classification from Lania et al 2001):⁹

	AHO	Hormone resistance	GNAS1 defect
PHP1a	Yes	Multiple	Yes
PPHP	Yes	None	Yes
PHP1b	No	PTH	Yes
PHP1c	Yes	Multiple	No
PHPII	No	PTH	No

Our patient had pseudohypoparathyroidism type 1a (PHP1a), also known as AHO. This was first described by Albright in 1952.¹⁰ These patients have a characteristic phenotype including short stature, centripetal obesity, brachydactyly, subcutaneous calcifications, depressed nasal bridge, hypertelorism, developmental delay and mental retardation.

It occurs due to the reduced activity of the Gs alpha protein. This is coded on the GNAS gene, which is located on chromosome 20q13 and contains 13 exons.¹¹ There are various mutations reported. It shows an autosomal-dominant inheritance. In the case of maternal transmission, children develop PHP1a. In paternal transmission, they develop pseudopseudohypoparathyroidism, characterised by signs of AHO and Gs alpha protein deficiency without biochemical evidence of hormone resistance. This is due to imprinting as a regulatory mechanism for Gs alpha transcription. Predominant maternal expression of Gs alpha has been documented in the thyroid gland,^12–14 gonads¹⁵ and pituitary.¹⁶

Gs alpha is a ubiquitously expressed signalling protein which stimulates the second messenger adenylyl cyclase when activated by an agonist-occupied G protein-coupled receptor. Many physiological processes rely on the normal functioning of this protein.¹¹ This explains the additional hormonal abnormalities that includes hypothyroidism and hypogonadism. Growth hormone deficiency is a common hormonal abnormality in PHP-1a patients, indicating resistance at the GHRH in pituitary somatotrophs.¹⁵

There has been only one previous case of retinal changes in PHP.¹⁷ In this case report, a 41-year-old woman with Albright's hereditary osteodystrophy with extensive cerebral calcification and visual impairment is described. The ERG abnormality suggested a retinopathy involving mostly rods, which was similar to our case. This condition is due to a genetic deficiency in G protein, and perhaps there is also involvement of another G protein-transducin in rods and cones, which has not been previously recognised as being involved in this condition.

Learning points.

• Sclerochoroidal calcification is characterised by typical geographic yellow white fundus lesions that usually occur bilaterally in adults and is normally asymptomatic.

• Its differential diagnosis includes a number of intraocular tumours such as choroidal metastasis, choroidal melanoma, lymphoma, choroiditis and choroidal osteoma. Calcification can be dystrophic or metastatic.

• Screening should be carried out to exclude an underlying systemic disorder such as pseudohypoparathyroidism.

• Sight-threatening complications that have been reported with sclerochoroidal calcification include choroidal neovascularisation and serous detachments.

• The electroretinogram abnormality suggests a retinopathy involving mostly rods which may be due to the involvement of the G proteins involved in normal photoreceptor functioning.