Neuropsychiatric phenotype in a child with pseudohypoparathyroidism.

Pseudohypoparathyroidism (PHP) is a rare heterogeneous genetic disease characterized by end-organ resistance to parathyroid hormone. In adulthood, heterogeneous neurological and psychiatric disorders have been reported which are associated with hypoparathyroidism in general and with PHP in particular, while for childhood, data are scanty. We report a case of a boy with PHP type 1b, in whom neurological signs at the onset prevailed, characterized by tic-like dyskinesias associated with a series of heterogeneous not well-defined neurological and behavioral features, describing the diagnostic work-up performed and the follow-up. We suggest that the diagnostic hypothesis of PHP might be considered when dealing with a child with tic-like dyskinesias, especially if associated with a series of heterogeneous not well-defined neurological and behavioral features. In these cases, treatment with calcitriol and calcium has to be started as soon as possible to achieve a prompt and persistent clinical improvement.

Introduction

Pseudohypoparathyroidism (PHP) is a rare heterogeneous genetic disease characterized by clinical and laboratory findings of hypocalcemia and hyperphosphatemia, with high plasmatic levels of parathyroid hormone (PTH) due to target tissue resistance, that activate cyclic adenosine monophosphate-dependent pathways via the alpha subunit of the stimulatory G protein.[1]

Several clinical subtypes of PHP have been described [Table 1].[2] In most cases, there is a molecular alteration within or upstream of the imprinted guanine nucleotide-binding protein, alpha-stimulating (GNAS) gene, located on chromosome 20q13.32, encoding the stimulatory G protein α-subunit. This protein couples the PTH receptor to adenylyl cyclase.

Table 1

Pseudohypoparathyroidism subtypes (modified from Levine, 2013)

PHP type I is classically further differentiated according to the presence (PHP Ia and Ic) or absence (PHP Ib) of clinical features of Albright hereditary osteodystrophy.[2]

In adulthood, heterogeneous neurological and psychiatric disorders have been reported that are associated with hypoparathyroidism in general and with PHP in particular, often with overt clinical manifestations such as complaints of tetany, generalized tonic-clonic convulsions, signs of increased intracranial pressure, intellectual disability, extrapyramidal syndromes, and psychosis. These reports are lacking as regards childhood.[34567]

We describe the neuropsychiatric phenotype of a child affected by PHP presenting with a tic-like pattern of dyskinesias.

Case Report

The patient, a male, was born at 41 weeks of gestation by oxytocin-induced delivery, after a pregnancy complicated by bleedings during the first 2 months and uterine contractions from the 7th month. At birth, he had normal respiratory adaptation, showed a mild jaundice, and weighed 4300 g (>97th centile for gestational age).

The parents were normal and not consanguineous. The family history was positive for cerebral calcifications of undefined origin in the maternal grandfather, discovered in later life after an episode of transient amnesia; probable cognitive impairment, appearing at the age of 70 years, in the maternal great-grandfather.

In the following years, patient's weight, height, and growth of cranial circumference were in the normal range for the general population. Psychomotor development was normal except for a mild language delay. The child is bilingual. The academic performance has been good so far. From the age of about 3 years, the child presented sensory hypersensitivity (sight, hearing, and smell), irritability, and tantrums. At that time, the neurobehavioral assessment excluded a developmental disorder, and no medical examinations were performed. Subsequently, the aforementioned behavioral problems disappeared. Clumsiness was referred. The child reported a backache. From 9 years and 2 months of life, he began showing ocular motor tics similar to twitching eyelids. From the age of 9 years and 9 months, the boy showed episodes characterized by sensation of throat tightness lasting for a few seconds. He also showed general fatigue. At the age of 9 years and 10 months, while using a personal computer, he had a paroxysmal event characterized by dizziness and lateral deviation of the left eye with diplopia, lasting for about 10 s apparently without loss of consciousness; about 3 h later, he had a sensation of throat tightness. The next day, he came to our attention. The electroencephalogram showed polymorphic low-to-medium amplitude delta activity mixed with medium amplitude sharp waves over bilateral temporal regions prevailing on the right hemisphere. The brain computerized tomography (CT) scan revealed multiple bilateral subcortical focal mineralizations, basically symmetrical, involving also the lenticular nucleus and thalamus bilaterally [Figure 1a]. Neurological examination showed hypomimia, ocular motor tics, and slight awkwardness in tandem gait. Blood calcium was 6.7 mg/dL (normal values: 8.5–10.5), ionized calcium was 0.75 mmol/L (1.13–1.32), phosphorus was 9.1 mg/dL (3.7–5.6), PTH was 369 pg/mL (15–65), and creatine phosphokinase was 422 U/L (<170). Magnesium level was normal. Thyroid-stimulating hormone (TSH) was 7.72 µIU/mL (0.27–4.20), while free triiodothyronine and free thyroxine were normal; screening for celiac disease was negative; anti-parathyroid, anti-thyroglobulin, anti-thyroid peroxidase, anti-TSH receptor antibodies, and thyroglobulin were all normal. Brain magnetic resonance imaging (MRI) (3 Tesla) with gadolinium confirmed the presence of multiple mineralizations on T2 sequences and showed Chiari type 1 anomaly on sagittal T1 sequences [Figure 1b]. Six months later, MRI showed that Chiari anomaly was unchanged. Full spine MRI excluded syringomyelia. The neck ultrasonography showed normal thyroid and submandibular glands; in both parathyroids, there were multiple formations (probable lymph nodes). The X-ray of the skeleton showed a relative brachymetacarpia of the fourth and fifth fingers [Figure 1c] and diffuse osteopenia. Physical examination showed round face, prominent metopic ridge, depressed nasal bridge, thin habitus, long arms and legs, cubitus valgus, short IV and V metacarpals, adduced shoulder, and mild scoliosis. Clinical aspects, radiological features, and laboratory findings suggested the hypothesis of PHP. The absence of typical signs of Albright hereditary osteodystrophy led to hypothesize PHP type Ib. In fact, molecular analysis of GNAS1 gene did not show mutations in the exon sequence, but demonstrated multiple alterations in the methylation patterns. Genetic testing gave negative results in both parents, which is compatible with a de novo PHP type Ib.

Figure 1

(a) Axial brain computerized tomography scan showing multiple bilateral subcortical focal mineralizations, basically symmetrical, involving also lenticular nucleus and thalamus bilaterally. (b) Sagittal T1 brain magnetic resonance imaging (3 Tesla) showing Chiari type 1 anomaly. (c) X-ray of the hand showing a relative brachymetacarpia of the fourth and fifth fingers

Neuropsychological assessment showed full intelligence quotient (IQ) = 91 (verbal IQ = 89 and performance IQ = 96: no significant gap) (Wechsler Intelligence Scale for Children – Third Edition).

At the age of 9 years and 11 months, an oral supplementation with calcitriol (0.25 µg/day) and calcium (500 mg/day) was started. During the following 6 months, there were no further paroxysmal events with ocular deviation, tic-like dyskinesias gradually disappeared, and general fatigue decreased, simultaneously with the normalization of blood calcium, phosphorus, and creatine phosphokinase, while PTH decreased to 89 pg/mL (15–65) and TSH decreased to 6.75 µIU/mL (0.27–4.20).

Discussion

So far, the neuropsychiatric disorders associated with hypoparathyroidism in general and with PHP in particular have been sparsely described in children. Paroxysmal dyskinesias have been reported in some cases, adults or children, with PHP,[47] but in no case does the clinical picture seem to be characterized mainly by tic-like symptoms as in our patient. In the diagnostic work-up of our case, the key moment was the unexpected discovery of cerebral calcifications through the CT scan performed due to the abnormalities of the electroencephalogram, carried out following a paroxysmal event resembling an epileptic seizure. Neuroimaging data led us to study bone metabolism by laboratory and radiographic evaluations to confirm the hypothesis of PHP type 1.[28] Moreover, this hypothesis was supported by an accurate dysmorphic evaluation; the round face and the short metacarpals in the absence of more typical signs of Albright hereditary osteodystrophy led to a clinical diagnosis of PHP type 1b. This diagnosis was confirmed by genetic testing, which showed methylation defects in the GNAS locus compatible with a sporadic PHP type Ib. In our patient, the hypothesis of a cause and effect relationship between the endocrinological disorder and the neurological symptomatology has been suggested also by the prompt and persistent improvement of dyskinesias after normalization of calcium metabolism induced by the supplementation with calcitriol and calcium. In our case, we hypothesize a correlation between serum calcium levels and tic-like dyskinesias, similarly to what other authors have done for paroxysmal dyskinesias.[7] But also, other clinical aspects detected in our case deserve to be discussed. The general fatigue of our patient looks similar to what has been reported for the boy with PHP type 1b (unlike our case, due to a microdeletion involving exons 4–6 of the GNAS neighboring Syntaxin 16 gene) described by Nagasaki et al. in 2013,[9] in whom neuromuscular symptoms prevailed and there was an increase in creatine phosphokinase. Also this symptomatology improved in our case after the start of supplementation with calcitriol and calcium, simultaneously with the normalization of creatine phosphokinase. The finding of Chiari type 1 anomaly is unclear. In 2011, Martínez-Lage et al. reported a case of PHP type Ia with Chiari type 1 anomaly, hypothesizing the pathogenetic role of skull changes.[10] Obviously, in our case, in the absence of these bone alterations, a different pathogenetic mechanism should be hypothesized to explain aspects such as a gradient between intracranial and spinal pressure. Alternatively, in our case, Chiari anomaly should be considered as an incidental finding. Finally, we can speculate that also the behavioral problems manifested by the child around the 3rd year of life may be related to a probably not severe hypocalcemia, according to literature.[11] However, at that time, the dosage of serum calcium was not carried out.

Conclusion

We suggest that the diagnostic hypothesis of PHP, which is easily screenable by determining blood electrolytes, might be considered when dealing with a child with tic-like dyskinesias, especially if associated with a series of heterogeneous not well-defined neurological and behavioral features. In these cases, treatment with calcitriol and calcium has to be started as soon as possible to achieve a prompt and persistent clinical improvement.

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Conflicts of interest

There are no conflicts of interest.