Hypocalcemic Recurrent Generalized Seizures with Bilateral Basal Ganglia and Frontal Calcification as the Initial Manifestation of Albright's Hereditary Osteodystrophy in a Child: A Pictorial and Video-graphic Representations.

Albright hereditary osteodystrophy (AHO) is a hereditary metabolic disorder that presents with seizure secondary to hypocalcaemia. A careful phenotypic assessment of patients presenting with seizure clues to the diagnosis of AHO. The characteristic features are short stature,obesity and brachydactyly.Pseudohypoparathyroidism (PHP) is observed in patients with AHO and is characterized by inability of the body to respond appropriately to parathormone, mainly characterized by hypocalcaemia, increased serum parathormone concentration, insensitivity to the biological activity of parathormone, and hyperphosphatemia. In this study, we report a 14-year-old boy with distinctive phenotype of AHO, oral manifestations, and signs of tetany with PHP presenting as recurrent generalized seizure. Copyright:

Case Report

A 14-year-old boy of non-consanguineous parentage, first in birth order, a full-term born by normal vaginal delivery, had presented with history of two episodes of generalized tonic-clonic seizures of 1h duration. There was no prior history of fever, vaccination, or trauma. He had history suggestive of carpopedal spasm at age of four years for which he was not evaluated. Further interview with his parents revealed that he had low scholastic performance and was in eighth standard when he presented to us. Physical examination revealed blood pressure of 100/70mm Hg, pulse rate of 100 beats per minute, hypertelorism, broad facies with moderately low IQ (48) for age, malerupted teeth [Figure 1], and subcutaneous calcification over the flexor aspect of left wrist [Figure 2]. Anthropometry revealed height of 134 cm (less than third percentile), arm span of 123 cm, weight of 35kg, and widened bilateral thumb with short fourth and fifth fingers with dimpling of fist at fourth and fifth metacarpophalangeal joint (knuckle dimple sign) feature characteristic of brachydactyly [Figure 3A]. The skin over sole of feet was dry and crackled [Figure 3B]. His neurological examination showed positive bilateral Chvostek’s sign [Video 1], positive Trousseau’s sign [Video 2], and positive Woltman’s sign (delayed ankle jerk tendon relaxation) [Video 3]. The cranial nerves, sensory, motor, and cerebellar system examinations showed no abnormalities. The cardiovascular, respiratory, and abdominal system examinations were also found to be normal.

Figure 1

Hypertelorism, broad flattened nose, and malerupted teeth

Figure 2

Multiple subcutaneous calcification in the wrist marked with arrow

Figure 3

(A) Broad and shortened thumb with characteristic shortened fourth fingers bilaterally suggesting brachydactyly. (B) Cracked and dry feet marker of hypothyroidism

The biochemical evaluation of patient revealed hypocalcaemia with mild hyperphosphatemia, hypothyroidism, hypovitaminosis D3, and hyperparathyroidism [Table 1]. The liver function test, renal function test, and ultrasound examination of abdomen remained normal. Computed tomography of brain showed bilateral basal ganglion calcification and subcortical frontal curvilinear calcification [Figure 4].

Table 1

Abnormal laboratory tests

Biochemical test	Patient value	Normal value
Serum calcium	6.7 mg%	(8.4–10.2)
Serum phosphorous	5.2 mg%	(3.5–5.0)
Intact parathyroid hormone (iPTH)	440.1 pg/mL	11.1–79.5
TSH	>60.00 IU/mL	(0.7–5.7)
T4	57.72 nmol/L	(71–151)
T3	1.32 nmol/L	(1.3–3.3)
25 hydroxy vitamin D	<8.1ng/mL	deficient: <10ng/ mL, insufficient: 10–30,
sufficient: 30–100, intoxication: >100
ESR	First hour 70 mm	Second hour 120 mm
Hb	10.5g/dL	11–15.5

iPTH = intact parathyroid hormone; TSH = thyroid stimulating hormone; ESR = erythrocyte sedimentation rate; Hb = hemoglobin

Figure 4

Bilateral basal ganglion calcification (marked with black arrow)

Based on the history, lab parameters and characteristic physical features a provisional diagnosis of pseudohypoparathyroidism(PHP) and AHO was considered. Child was given intravenous levetiracetam infusion at 40mg/kg body weight for the control of seizure. Later maintenance dose of levetiracetam was given at 20mg/kg/day in 2 divided doses. Intravenous calcium gluconate infusion was given as child had features of hypocalcemic tetany (positive bilateral Chvostek’s sign, positive Trousseau’s sign). He was also given maintenance oral calcium supplements for correction of hypocalcemia. Oral vitamin D and thyroid replacement was done for correction of vitamin D deficiency and hypothyroidism respectively. The child was seizure free during the subsequent visits. There was a considerable increase in serum calcium level to 8.8 mg%, serum phosphate level was 4.7 mg%, which was reduced compared to initial values, and PTH levels were 300.5 pg/mL, which showed a considerable reduction from the aforementioned values. The follow-up at four months interval showed an improvement in scholastic performance and IQ of 55.

Discussion

In 1942, Fuller Albright introduced the term PHP to describe the PTH resistance in patients with AHO present with hypocalcaemia and hyperphosphatemia along with varied developmental and skeletal defects.[1] In a survey conducted in 1998, the prevalence of PHP in Japan by was 3.4 cases per million.[2] There are no data regarding the prevalence of PHP in the world. PHP is an uncommon sporadic or inherited genetic disorder, which is subdivided into several distinct entities (type Ia, Ib, Ic, type II). All these subtypes of PHP are caused by mutation or imprinting abnormalities in the stimulatory G protein (Gsα). These are caused by molecular defects on the gene (GNAS1) encoding the alpha subunit of the Gsα.[3] AHO occurs twice as frequently in females as in males.

AHO is a syndrome with a broad range of manifestations including round face, short stature, subcutaneous (under the skin) ossifications (gradual replacement of cartilage by bone), shortening and widening of the bones in the hands and feet (brachydactyly). The characteristics of AHO are related with mental retardation, resistance to parathyroid hormone (PHP), and to other hormones (thyroid-stimulation hormone, in particular).[4] Oral manifestations in patients with AHO include aplasia, thin enamel with enlarged pulp chamber hypoplasia, hypodontia, pulp calcification, multiple carious teeth, multiple unerupted teeth, crowded anterior teeth, anterior open bite, gingival hyperplasia, and gingivitis with spontaneous bleeding and pain.[5] Treatment consists of calcium and vitamin D supplements to maintain total serum and ionized calcium levels within the reference range, to avoid hypercalciuria and to suppress PTH levels.[6] Thyroid hormone replacement should be done for correction of hypothyroidism.

Our patient presented with recurrent seizure, and the work up showed that patient was found to have PHP Ia. In patients with Pseudohypoparathyroidism type Ia (PHP Ia), serum calcium will be low, with high serum phosphorus and serum PTH levels, with low activity of Gsα and with multihormone resistance and physical features of AHO. The cause of the patient’s seizure activity was multifactorial in the present case. These included direct and indirect effects of PHP, as well as vitamin D deficiency, extensive calcifications of the basal ganglia, and cerebral cortex and hypothyroidism.

Basal ganglion and subcortical curvilinear calcification is a rare phenomenon in children and should be investigated for defects of calcium metabolism. Eighty percent of the cases have defects in calcium metabolism such as PHP and hypoparathyroidism.[78] Symmetrical basal ganglion calcification in children are pathological and causes include central nervous system infections, hypoxia, poisoning, Cockayne syndrome, down syndrome, tuberous sclerosis, and metabolic diseases. None of these conditions may have derangement in calcium and phosphorus, except metabolic disease. Among the metabolic causes are hypoparathyroidism, PHP, pseudoPHP, hyperparathyroidism, and hypothyroidism. Our patient had laboratory and physical features of AHO that clued toward the diagnosis of PHP.

Conclusion

Children presenting with seizure physical examination clue to very important diagnosis as observed in the present case. Metabolic work up is mandatory in cases where imaging brain shows basal ganglion and subcortical calcification. Calcium, vitamin D, and thyroid hormone replacement may be required for life-long to maintain calcium homeostasis and prevent progression of disease.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.