Indian Pediatrics 2012;49:989-991http://www.indianpediatrics.net/dec2012/989.pdf
Pseudohypoparathyroidism with Diabetes Mellitus and Hypothyroidism
Bedangshu Saikia, Himanshu Aneja, Sunaina Arora, Jacob M Puliyel.
Dept of Pediatrics, St Stephens Hospital, Tis Hazari, Delhi-110054, India.
Dr Bedangshu Saikia
Dept of Pediatrics, St Stephens Hospital, Tis Hazari, Delhi-110054, India
Albright's Hereditary Osteodystrophy (AHO), Pseudohypoparathyroidism (PHP), Pseudopseudohypoparathyroidism (PPHP), Parathyroid hormone (PTH), Vitamin D Deficiency, Insulin Dependent Diabetes Mellitus (IDDM), Hypothyroidism, Genetic imprinting
1130 (excluding title page, abstract/summary, references, figures and tables)
All author contributed write up of this case report
We report the case of 12 year old child with pseudohypoparathyroidism (PHP) whose mother had pseudopseudohypoparathyroidism. The child had low serum calcium, high phosphorous and high parathormone levels. PHP occurs due to a defect in the guanine nucleotide binding protein (G protein). She also had hypothyroidism which is known to utilise the G protein pathway. She developed insulin dependent diabetes mellitus (IDDM) while under follow-up. Rat models have suggested that insulin is another peptide hormone which works through G protein. However this is arguably the first time IDDM has been reported associated with PHP.
Insensitivity to parathormone (PTH) in PHP results from a defect in the stimulatory G protein needed for activation of cyclic adenosine monophosphate (cAMP) . The same G protein is also needed for activity of a number of other peptide hormones. PHP associated with poor responsiveness to thyroid stimulating hormone, gonadotrophin, glucagon, corticotrophin and vasopressin have been reported previously [2, 3]. Although insulin is another peptide hormone, association of PHP with diabetes mellitus has not been reported previously. We report a child with PHP with hypothyroidism and diabetes mellitus. This child also had vitamin D deficiency. Maternal imprinting of the defective gene is suggested by the fact that she inherited the disorder from her mother who has PPHP .
A 12 year old girl born to a non-consanguineous marriage presented to our hospital with a 1 year history of multiple episodes of generalised seizures and tetany. She had a history of poor scholastic performance and gradual development of subcutaneous nodules over abdomen. On examination, she was noted to have a round chubby face, short neck, short stubby hands and feet [Fig 1]. Her height was 136 centimetres (below 3rd percentile for age, being 50th centile for 10-year-old girls). Her weight was 37 kilograms corresponding to the 25th percentile for age. Her body mass index (BMI) was 20. Four hard subcutaneous nodules were palpable over the abdomen (0.7cms to 1.8 cms in size). Chvostek’s and Trousseaus’s sign were positive. Sexual Maturity Rating (SMR) was Stage 2 (normal for age).
Table 1 shows the results of her laboratory investigations. Total serum calcium was low (3mg/dl) and serum phosphorus was raised (11.17 mg/dl). Serum alkaline phosphatase was raised (565 U/L) as was her serum parathyroid hormone levels (468 pg/ml). Urinary calcium level was decreased (0.5 mg/dl). Radiograph of the hands and feet showed marked shortening of the metacarpals and metatarsals [Fig 2A & 2B]. Neuroimaging of the brain revealed intracranial striopellidodentate calcification [Fig 2C]. Histopathologic examination of the nodules revealed small spicules to large masses of mature bone in the dermis suggestive of primary subcutaneous calcification [Fig 2D]. Her thyroid function tests were abnormal with low free thyroxin (FT3) (1.52 pg/ml), low total thyroxin (FT3) (42.2 ng/ml) and raised thyroid stimulating hormone (TSH) levels (12.3ul/ml). She also had low 25 – OH vitamin D3 levels (9 ng/ml ).
She was treated initially with intravenous (IV) sodium valproate to control seizures along with IV calcium and intramuscular vitamin D (Inj Arachitol – 6 hundred thousand units). Later, medications were changed to oral calcium (2 gm daily) and vitamin D (alphacalcidol 2 mcg daily). Associated hypothyroidism was treated with 50 mcg levothyroxine daily.
Her mother also had abnormal morphological features, round facies, short stature (height of 145 centimetres) and brachydactyly of fingers and toes [Fig 1]. Her serum calcium, phosphorus and alkaline phosphatase levels were normal [Table 1]. It was reported that the mother’s father was phenotypically similar to her. There is no history of convulsions in the mother’s father. He died about ten years before his granddaughter reported to us.
Two months after initial presentation, the child was readmitted with diabetes mellitus. Her serum C-Peptide levels were low (0.24 ng/ml against a reference range of 1.1 – 5.0 ng/ml) suggesting insulin dependent diabetes mellitus. She was put on subcutaneous insulin. Her blood sugars levels are well controlled on this.
Pseudohypoparathyroidism (PHP) manifests on account of genetic defects in the hormone receptor adenylate cyclase system such that parathormone (PTH) does not raise the level of calcium or lower the level of phosphorous. In Type 1a PHP the defect is in the G protein which is a coupling factor for PTH to activate cAMP. The G-protein defect can impact a large number of hormones besides PTH [2, 3]. PHP Type Ia is inherited from the mother. Patients are characteristically short statured with stocky habitus, obesity, round facies, brachydactyly and soft-tissue calcification. These features are typically known as the Albright Hereditary Osteodystrophy (AHO) phenotype . Striopallidodentate calcification, although uncommon helps confirm the diagnosis of Type 1a PHP . PHP Type Ib does not have the AHO phenotype and there is no resistance to other G-protein coupled hormones. PPHP patients have features similar to Type Ia PHP but without biochemical evidence of PTH resistance . Our patient has features of Type Ia PHP, including osteoma cutis and striopallidodentate calcification. Her mother has features of PPHP.
Primary hypothyroidism and hypogonadism are the associated hormone defects that occur most commonly. Typically hypothyroid patients have an elevated serum TSH, low or low normal serum thyroxine (T4) levels, low antithyroid antibody levels and they don’t manifest with goitre. Hypothyroidism may be apparent earlier in life, prior to the development of hypocalcaemia of PHP. Reproductive dysfunction in the form of delayed puberty, oligomenorrhoea and infertility may also occur [8, 9, 10]. Our patient had hypothyroidism. The sexual maturity rating (SMR) was normal for age. She had not attained menarche at 12 years of age.
Insulin is one of the peptide hormones which work through G protein. This has been demonstrated in animal models (Zucker rats) of both insulin dependent and non insulin dependent diabetes [11, 12]. However diabetes has not been associated with PHP in humans previously. The child reported here had low serum C-peptide level, suggestive of insulin dependent diabetes mellitus. More studies are required to understand the mechanism underlying this phenomenon.
The child also had low vitamin D levels (25 – OH vitamin D). Primary vitamin D deficiency is not uncommon in Delhi [13, 14, 15]. Coincident hypovitaminosis D is a possibility in this child. Hypovitaminosis D by itself can result in low calcium and elevated PTH levels similar to PHP. However the other phenotypical features of PHP cannot be explained by vitamin D deficiency.
The child's maternal grandfather was also short “with features like the mother”, suggesting he probably had either PPHP or PHP (the grandfather was not tested to determine if he had hypocalcaemia). The sequence of inheritance in this pedigree adds credibility to the suggestion that the disorder is influenced by imprinting in a parent-of-origin dependent manner. The defective gene is a dominant gene. However if it is inherited from the father the gene is only partially expressed (PPHP). If on the other hand the gene is inherited from the mother it is fully expressed (PHP). Even if the gene is only partially expressed it has potential to be fully expressed in the next generation depending on the sex of the parent transmitting the gene [4, 16]. In this family study, the index case acquired the disease (PHP) from her mother who had PPHP. She in turn inherited PPHP from her father.
We hope this report will help understand this complex disorder and its protean manifestations better.
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