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• Pseudohypoparathyroidism, movement disorder, and non-organic disease
  Frederic Perez-Alvarez
  Published on: 13 April 2016

• Published on: 13 April 2016

  Pseudohypoparathyroidism, movement disorder, and non-organic disease

  • Frederic Perez-Alvarez, Pediatric Neurologist

  Dear Editor,

  We read with great interest the recent article by Stone et al (1) on functional symptoms and signs in neurology. Pseudohypoparathyroidism is a rare disease. In 1998, a nationwide epidemiologic survey of PHP was conducted in Japan based on hospital visits in 1997; the period prevalence was 3.4 cases per 1 million people (2). No information is available regarding prevalence in the rest of the world. Pat...

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  Dear Editor,

  We read with great interest the recent article by Stone et al (1) on functional symptoms and signs in neurology. Pseudohypoparathyroidism is a rare disease. In 1998, a nationwide epidemiologic survey of PHP was conducted in Japan based on hospital visits in 1997; the period prevalence was 3.4 cases per 1 million people (2). No information is available regarding prevalence in the rest of the world. Patients' ages range from infancy to senescence (3). Frequently, it is misdiagnosed.

  Recently, we have seen a 6 years-old female, second child of unrelated African parents. On admission, clinical findings included involuntary changing movement of both arms and legs, mimicking several conditions. Conscious estate was normal. Chvostek sign, Trousseau sign, and dimpling over the knuckles of a clenched fist (Archibald sign for brachydactiyly) were all absent.

  Routine laboratory findings were normal apart from low serum calcium (serum total calcium 50 mg/l and ionized calcium 28 mg/l ) and elevated serum phosphate ( 70 mg/l). QT interval of the ECG, and EEG were normal. Magnetic resonance image was normal and CT scanning did not show calcification of the basal ganglia. Further studies included normal skeletal radiologic study, not showing small soft tissue opacities (calcifications / ossifications) either, elevated serum concentration of intact PTH by immunoradiometric assay (IRMA) and no responsiveness to PTH by measurement of changes in serum calcium, phosphorus, cAMP, and calcitriol concentrations and in urinary cAMP and phosphorus excretion after administration of the biosynthetic N-terminal fragment of PTH. On the other hand, thyroid function tests and measurement of gonadotropin and testosterone or estrogen levels, in addition to growth hormone function assessed by insulinlike growth factor-1, and calcitoninemia were all normal.

  Oral calcium and 1alpha-hydroxylated vitamin D metabolites, such as calcitriol, was initiated with a diagnosis of PHP. Six months after the treatment, the girl was in good overall condition. She is asymptomatic and the neuromuscular examination has normalized. Bone mineral density is also normal.

  PHP is a heterogeneous group of disorders characterized by hypocalcemia (often asymptomatic), hyperphosphatemia, increased serum concentration of parathyroid hormone (PTH), and insensitivity to the biological activity of PTH. It is classified into 1a, 1b, and 2. The 1a correspond to the classical Albright hereditary osteodystrophy (AHO). Brachydactyly is the most reliable sign in the diagnosis of AHO. There is deficiency in Gsa protein that enhance cAMP production. Different peptide hormones use the alpha subunit of the Gsa protein. Mentation is impaired in approximately half of patients with PHP type 1a and appears to be related to the Gsa deficiency rather than to chronic hypocalcemia because patients with other forms of PHP and hypocalcemia have normal mentation.. Patients with pseudo-PHP have the phenotype of AHO but with normal biochemical parameters. Patients with pseudo-PHP are often found in the same kindreds as those with PHP type 1a.

  Patients with PHP type 1b have a genetically and biochemically distinct disorder. They present with hypocalcemia without AHO. The severity of hypocalcemia can vary greatly among family members of the same kindred. They have normal expression of Gsa protein in accessible tissues, and manifest hormonal resistance limited to PTH target tissues. PTH resistance may be limited to the kidney, with PTH responsiveness preserved in the bone, as evidenced by the hyperparathyroid skeletal lesions observed in these patients. The severity can vary considerably from one patient to another; even within a single kindred Members of the affected family who share the same haplotype in band 20q13.3 have been reported to be clinically asymptomatic and to have serum calcium levels within the reference range. Patients with PHP type 2 show no skeletal and developmental defects, similar to patients with PHP type 1b, but they show a normal urinary cAMP response. As previously reported, our patient was suspected to have seizure, movement disorder (3,4) and functional non-organic disease. A purely symptom-oriented approach, concentrating only on the "seizures", may lead to the wrong diagnosis. As in the general rule in medicine, the essential part of the investigation is the history. It is a truism that seizures occurring many times a day in the presence of a normal interictal EEG are most likely to be non-epileptic. However, the presence of paroxysmal abnormalities on the EEG do not necessarily prove a diagnosis of epilepsy, and it should be recalled that spike-wave paroxysmal discharges are found in approximately 3% of healthy people. In particular, paroxysmal theta activity or sharp waves, especially in the posterior temporal location should not be misinterpreted as confirming a clinical impression that the patient has epilepsy.

  Movement disorder is an heterogeneous entity that demands expertise for a correct diagnosis, which, on the other hand, may be difficult because the terms have not been uniformly applied by different authors. Our patient showed dyskinetic movements (3) as an abnormal or disordered movement as those seen in disorders affecting the extrapyramidal system as in parkinsonism (4) or phenotiazine intoxication. Also, widespread, arrhythmic, involuntary movements of a forcible, rapid, jerky type and of brief duration, as seen in Sydenham's and Huntington's chorea., and involuntary athetoid movements characterized by recurrent, slow, wormlike, and more or less continual change of position of the fingers, toes, hands, feet, and other parts of the body, as seen chiefly in cerebral palsy and kernicterus, as well as after encephalitis, toxic encephalopathies, and cerebrovascular accidents. Our patient also showed myoclonic movements in the form of exceedingly abrupt, shocklike contractions of muscles, irregular in rhythm and amplitude and asynchronous or asymmetrical in distribution. And also, tremulous movements in the sense of a more or less regular, rhythmic oscillation of a part of the body around a fixed point involving alternate contraction of agonist and antagonist muscles. Finally, we observed also rigidity in the sense of a form of hypertonus in which the muscles are continuously or intermittently tense. In contrast to spasticity, the increase in tone has a uniform quality throughout the range of passive movement of the limb. We must keep in mind these considerations not to misdiagnose this entity (5).

  Perez-Alvarez F a, Mayol Ll b, Luque A b, Peña A b

  a Pediatric Neurology
  b Pediatrics
  Hospital Universitari ICS Dr J Trueta
  Girona, Spain
  E-mail: fpereza@comg.es

  References

  1. Stone J, Carson A, Sharpe M. Functional symptoms and signs in neurology: assessment and diagnosis. J Neurol Neurosurg Psychiatry 2005; 76: 2-12.

  2. Nakamura Y, Matsumoto T, Tamakoshi A, Kawamura T, Seino Y, Kasuga M, Yanagawa H, Ohno Y: Prevalence of idiopathic hypoparathyroidism and pseudohypoparathyroidism in Japan. J Epidemiol 2000; 10: 29-33.

  3. Mahmud FH, Linglart A, Bastepe M, Juppner H, Lteif AN. Molecular diagnosis of pseudohypoparathyroidism type Ib in a family with presumed paroxysmal dyskinesia. Pediatrics 2005; 115: e242-4.

  4. Pearson DW, Durward WF, Fogelman I, Boyle IT, Beastall G. Pseudohypoparathyroidism presenting as severe Parkinsonism. Postgrad Med J 1981 Jul; 57(669): 445-7.

  5. Carson AJ, Ringbauer B, Stone J, McKenzie L, Warlow Ch, Sharpe M. Do medically unexplained symptoms matter? A prospective cohort study of 300 new referrals to neurology outpatient clinics. J Neurol Neurosurg Psychiatry 2000; 68: 207-210.

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  Conflict of Interest:
  None declared.

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